phytoestrogens and Breast-Neoplasms

While endocrine therapy is considered as an effective way to treat breast cancer, it still faces many challenges, such as drug resistance and individual discrepancy. Therefore, novel preventive and therapeutic modalities are still in great demand to decrease the incidence and mortality rate of breast cancer. Numerous studies suggested that G protein-coupled estrogen receptor (GPER), a membrane estrogen receptor, is a potential target for breast cancer prevention and treatment. It was also shown that not only endogenous estrogens can activate GPERs, but many phytoestrogens can also function as selective estrogen receptor modulators (SERMs) to interact GPERs. In this review, we discussed the possible mechanisms of GPERs pathways and shed a light of developing novel phytoestrogens based dietary supplements against breast cancers.

Topics: Breast Neoplasms; Dietary Supplements; Estrogens; Female; Humans; Phytoestrogens; Receptors, Estrogen; Selective Estrogen Receptor Modulators

The human gut is a host for trillions of microorganisms, divided into more than 3,000 heterogeneous species that is called the gut microbiota. The gut microbiota composition can be altered by many different endogenous and exogenous factors, especially diet and nutrition. A diet rich in phytoestrogens, a variable group of chemical compounds similar to 17-β-estradiol (E2), the essential female steroid sex hormone is potent to change the composition of gut microbiota. However, the metabolism of phytoestrogens also highly depends on the action of enzymes produced by gut microbiota. Novel studies have shown that phytoestrogens could play an important role in the treatment of different types of cancers, such as breast cancer in women, due to their potential to decrease estrogen levels. This review aims to summarize recent findings about the lively dialogue between phytoestrogens and gut microbiota and to address their possible future application, especially in treating patients with diagnosed breast cancer. A potential therapeutic approach for the prevention and improving outcomes in breast cancer patients could be based on targeted probiotic supplementation with the use of soy phytoestrogens. A positive effect of probiotics on the outcome and survival of patients with breast cancer has been established. However, more in vivo scientific studies are needed to pave the way for the use of probiotics and phytoestrogens in the clinical practice of breast cancer treatment.

Topics: Biotransformation; Breast Neoplasms; Estrogens; Female; Gastrointestinal Microbiome; Humans; Isoflavones; Phytoestrogens

Phytoestrogens are plant secondary metabolite that is structurally and functionally similar to mammalian estrogens, which have been shown to have various health benefits in humans. Isoflavones, coumestans, and lignans are the three major bioactive classes of phytoestrogens. It has a complicated mechanism of action involving an interaction with the nuclear estrogen receptor isoforms ERα and ERβ, with estrogen agonist and estrogen antagonist effects. Depending on their concentration and bioavailability in various plant sources, phytoestrogens can act as estrogen agonist or antagonists. Menopausal vasomotor symptoms, breast cancer, cardiovascular disease, prostate cancer, menopausal symptoms, and osteoporosis/bone health have all been studied using phytoestrogens as an additional standard hormone supplemental remedy. The botanical sources, techniques of identification, classification, side effects, clinical implications, pharmacological and therapeutic effects of their proposed mode of action, safety issues, and future directions for phytoestrogens have all been highlighted in this review.

Topics: Animals; Breast Neoplasms; Estrogens; Humans; Isoflavones; Male; Mammals; Phytoestrogens; Prostatic Neoplasms; Receptors, Estrogen

Nuclear receptors (NRs) represent intracellular proteins that function as a signaling network of transcriptional factors to control genes in response to a variety of environmental, dietary, and hormonal stimulations or serve as orphan receptors lacking a recognized ligand. They also play an essential role in normal development, metabolism, cell growth, cell division, physiology, reproduction, and homeostasis and function as biological markers for tumor subclassification and as targets for hormone therapy. NRs, including steroid hormone receptors (SHRs), have been studied as tools to examine the fundamentals of transcriptional regulation within the development of mammals and human physiology, in addition to their links to disturbances. In this regard, it is widely recognized that aberrant NR signaling is responsible for the pathological growth of hormone-dependent tumors in response to SHRs dysregulation and consequently represents a potential therapeutic candidate in a range of diseases, as in the case of prostate cancer and breast cancer. On the other hand, phytosterols are a group of plant-derived compounds that act directly as ligands for NRs and have proven their efficacy in the management of diabetes, heart diseases, and cancers. However, these plants are not suggested in cases of hormone-dependent cancer since a certain group of plants contains molecules with a chemical structure similar to that of estrogens, which are known as phytoestrogens or estrogen-like compounds, such as lignans, coumestans, and isoflavones. Therefore, it remains an open and controversial debate regarding whether consuming a phytosterol-rich diet and adopting a vegetarian lifestyle like the Mediterranean diet may increase the risk of developing steroid hormone-dependent cancers by constitutively activating SHRs and thereby leading to tumor transformation. Overall, the purpose of this review is to better understand the relevant mechanistic pathways and explore epidemiological investigations in order to establish that phytosterols may contribute to the activation of NRs as cancer drivers in hormone-dependent cancers.

Topics: Animals; Breast Neoplasms; Estrogens; Humans; Male; Mammals; Phytoestrogens; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Steroids

Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women's Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.

Topics: Breast; Breast Neoplasms; Female; Humans; Isoflavones; Neoplastic Stem Cells; Phytoestrogens

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

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Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; 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Breast cancer is the leading form of cancer in women, which is also hormone- dependent. Depending on the receptor expression, these cancers are subdivided into different forms, and among these receptors, estrogen, progesterone, and Her2 are the important ones. Targeting breast cancer (BC) has been difficult due to their varied nature; however, various phytocompounds, especially those having estrogen-like properties, have proven to be effective.. The present review is aimed to provide a detailed description of various Phytocompounds inhibiting breast cancer proliferation and progression; emphasis has been given to the role of phytoestrogens with their molecular mechanism of action.. The data were collected from reputed databases, such as PubMed/Medline, Web of Science, Science Direct, Eurekaselect, etc. Data on the phytoestrogens were collected using individual names and "phytoestrogens" as keywords. Articles published in journals, which are not indexed by Thomson Reuters (SCI/SCIE/ESCI), were omitted.. Natural products are important drug candidates against multiple forms of breast cancer. In addition to the initiation and proliferation events, these molecules inhibit epithelial to mesenchymal transition (EMT) and metastasis of BC. Phytoestrogens are an important class of compounds which have known estrogenic potential; studies have also indicated the anticancer potentials of these molecules in cell culture and animal models of BC.. Natural plant compounds, especially phytoestrogens, are promising anti-breast cancer agents that induce cell cycle arrest, apoptosis, and autophagy-mediated cell death. However, more clinical studies are necessary so that these molecules can be used as commercial drug molecules.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Epithelial-Mesenchymal Transition; Female; Humans; Phytoestrogens

Cancer is the world's devastating disease, and breast cancer is the most common reason for the death of women worldwide. Many synthetic drugs and medications are provided with their beneficial actions, but all of these have side effects and resistance problems. Natural remedies are coming forward to overcome the disadvantages of synthetic drugs. Among the natural categories, phytoestrogens having a structural similarity of mammalian oestradiol proves its benefit with various mechanisms not only in the treatment of breast cancer but even to prevent the occurrence of postmenopausal symptoms. Phytoestrogens are plant-derived compounds that were utilized in ancient medications and traditional knowledge for its sex hormone properties. Phytoestrogens exert pleiotropic effects on cellular signalling and show effects on estrogen-dependent diseases. However, because of activation/inhibition of steroid hormonal receptor ER-α or ER-β, these compounds induce or inhibit steroid hormonal (estrogen) action and, therefore, have the potential to disrupt hormone (estrogen) signalling pathway. In this review, we have discussed and summarize the effect of certain phytoestrogens and their possible mechanisms that can substantiate advantageous benefits for the treatment of post-menopausal symptoms as well as for breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Screening Assays, Antitumor; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Flavonoids; Humans; Lignans; Phytoestrogens; Signal Transduction; Stilbenes; Structure-Activity Relationship; Sulfatases

There is a growing interest in diets and their effects on cancer prognosis. In 2014, a report from the World Cancer Research Fund on diet and women with a history of breast cancer did not demonstrate a major effect on breast cancer prognosis. The aim of this literature review was to provide an update of knowledge in this area.. Randomized trials, prospective cohorts and meta-analyses published between 2012 and 2018 examining the impact of diet on recurrence risk and/or mortality after breast cancer were included, to achieve the objective. We evaluated study quality (according to Haute Autorité de Santé criteria) and the studied diets were categorized: macronutrients, micronutrients and selective foods.. We selected eighteen articles that met levels of evidence 1 to 3. For macronutrients, a low-fat diet was associated with better survival. With regard to micronutrients, a diet rich in phytœstrogen reduced the risk of cancer recurrence. Finally, the adoption of a healthy diet was not associated with an improved prognosis for breast cancer but with an improvement in overall survival and risk of death from cardiovascular disease.. This review suggests that nutrition influences the prognosis of breast cancer. Nevertheless, the level of evidence of the results was insufficient to make recommendations. Ultimately, a healthy and balanced diet could be encouraged in order to reduce global mortality.

Topics: Breast Neoplasms; Cardiovascular Diseases; Cooking; Diet, Fat-Restricted; Diet, Healthy; Evidence-Based Medicine; Fasting; Female; Food; Humans; Inflammation; Malnutrition; Meta-Analysis as Topic; Micronutrients; Nutrients; Nutrition Policy; Nutritional Status; Nutritional Support; Phytoestrogens; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Risk

Genistein being a phytoestrogen imitates the characteristics of estrogen, which can be useful to treat conditions by reducing the estrogen levels at the time of menopause, osteoporosis and high risk for breast cancer.. The superior binding of genistein to ERβ might help in reducing breast malignancy risk.. Genistein induces cell cycle arrest, anti-metastatic properties and ultimately affects the breast cancer cell growth by multiple mechanisms. Genistein-mediated anti-proliferative or anti-growth effects are usually observed at higher concentrations. These signaling pathways involve the decrease of NF-κB, HIF-1α, VEGF, and an increase of tumor suppressor p21. This will provide further insight into understanding the biology of transcription factors NF-κB, and HIF-1α in breast cancer.

Topics: Breast Neoplasms; Cell Cycle Checkpoints; Cell Proliferation; Estrogen Receptor beta; Female; Genistein; Humans; Neoplasm Metastasis; Phytoestrogens; Signal Transduction

Selective estrogen receptor modulators (SERMs) are an increasingly important therapeutic modality that are used by clinicians on a daily basis. Unfortunately, clinicians have a limited understanding regarding the underlying mechanism(s) of how SERMs function and their increasingly useful role in the treatment of estrogen-responsive target tissues such as the breast, bone, vagina, uterine endometrium, and brain. This review will provide a basic understanding of our current knowledge of SERM pharmacodynamics and will highlight the clinical applications of Food and Drug Administration-approved SERMs in the treatment of vasomotor symptoms, osteoporosis, genitourinary syndrome of menopause, infertility, and breast cancer and its prevention. SERMs under development and natural phytoestrogens will also be reviewed.

Topics: Breast Neoplasms; Estrogens; Female; Humans; Osteoporosis; Phytoestrogens; Selective Estrogen Receptor Modulators

Breast cancer is the most common cancer occurring in women and causing the highest number of deaths among them. The role of xenoestrogens has been the subject of many studies in the pathogenesis of breast cancer. Less is known about the impact of xenoestrogens on the effectiveness of hormone therapy used to treat breast cancer, and thus possible drug-xenostrogen interactions.. The aim of this review is to summarize the current state of knowledge and present perspectives for further research on the impact of xenoestrogens on the effectiveness of drugs used in the treatment of hormone-dependent breast cancer.. Phytoestrogens, in particular flavonoid genistein, are the best studied group of xenoestrogens in terms of interaction with drugs used in the treatment of breast cancer, due to their frequent use, including their use in alleviating the adverse effects of hormone therapy. Analyzing the current state of knowledge, it seems that phytoestrogens intake should be avoided during conventional anti-cancer treatment. Of the other xenoestrogens, bisphenol A (BPA) is one of the best-tested compounds for interactions with drugs used to treat breast cancer. It has been shown that bisphenol A could reduced therapeutic effect of active tamoxifen metabolite and cytostatics used in breast cancer treatment.. Confirmation in clinical trials of the results obtained

Topics: Antineoplastic Agents; Benzhydryl Compounds; Breast Neoplasms; Female; Flavonoids; Hormones; Humans; Phenols; Phytoestrogens

Phytoestrogens, a class of plant-derived compounds that are structural mimics of estrogen, can bind to estrogen receptors, acting as either agonists or antagonists. They have been implicated in estrogen-mediated physiology, which makes them interesting targets of study, especially for biomedical applications in woman's health. The 1998 Women's Health Initiative sparked considerable interest in natural alternatives to hormone replacement therapy, thereby triggering many additional studies on phytoestrogens. In this review, key advancements in dietary phytoestrogens are addressed, emphasizing their relation to breast pathophysiology. Recent developments such as clinical trials, precise bioassays for screening and selection of potential phytoestrogens, drug delivery systems to enhance bioavailability of therapeutically favorable phytoestrogens, regulatory guidelines on phytoestrogen-based supplements, and avenues that need further improvement are also discussed.

Topics: Animals; Breast; Breast Neoplasms; Diet; Dietary Supplements; Drug Delivery Systems; Female; Humans; Phytoestrogens; Plant Preparations; Randomized Controlled Trials as Topic; Receptors, Estrogen

Breast cancer is one of the leading causes of cancer-related morbidity and mortality among women worldwide. Phytoestrogens, plant-derived polyphenols that structurally and functionally mimic 17β-estradiol, the mammalian estrogen hormone, are known to modulate multiple molecular targets in breast cancer cells. The structural and chemical similarities to estradiol enable phytoestrogens to exert estrogenic or antiestrogenic activities by binding to the estrogen receptors. Although phytoestrogens have low affinity for estrogen receptors, they are able to compete with 17β-estradiol for the ligand-binding domain of the receptors. Phytoestrogens trigger epigenomic effects that could be beneficial in breast cancer prevention and/or treatment. Few studies have focused on the cytotoxic and structure-activity relationships of phytoestrogen analogs and derivatives with more effective anticancer properties than their corresponding parent compounds. Phytoestrogens and their analogs and derivatives bind to estrogen receptors, with a preferential affinity for ERβ, and inhibit the growth promoting activity of ERα. These bioactive compounds also exert growth inhibitory effects through various cell signaling pathways. At the level of cell cycle, they inhibit the expression of oncogenic cyclin D1, increase the expression of cyclin-dependent kinase inhibitors (p21, p27, and p57) and tumor suppressor genes (APC, ATM, PTEN, SERPINB5). Phytoestrogens and their analogs and derivatives mediate their effects on breast cancer by inhibiting estrogen synthesis and metabolism, as well as exerting antiangiogenic, antimetastatic, and epigenetic effects. Furthermore, these bioactive compounds reverse multi-drug resistance. This review offers a comprehensive summary of current literature and future perspectives on the in vitro molecular mechanisms of the anticancer activities of phytoestrogens and their analogs and derivatives on breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estrogens; Female; Humans; Phytoestrogens; Receptors, Estrogen

Estrogens generated within endocrine organs and the reproductive system act as ligands for at least three types of estrogen receptors. Estrogen receptors α (ERα) and β (ERβ) belong to the so-called classical family of estrogen receptors, whereas the G protein-coupled receptor GPR30, also known as GPER-1, has been described as a novel estrogen receptor sited in the cell membrane of target cells. Furthermore, these receptors are under stimulation of a family of exogenous estrogens, known as phytoestrogens, which are a diverse group of non-steroidal plant compounds derived from plant food consumed by humans and animals. Because phytoestrogens are omnipresent in our daily diet, they are becoming increasingly important in both human health and disease. Recent evidence indicates that in addition to classical estrogen receptors, phytoestrogens also activate GPER-1 a relevant observation since GPER-1 is involved in several physiopathological disorders and especially in estrogen-dependent diseases such as breast cancer.The first estrogen receptors discovered were the classical ERα and ERβ, but from an evolutionary point of view G protein-coupled receptors trace their origins in history to over a billion years ago suggesting that estrogen receptors like GPER-1 may have been the targets of choice for ancient phytoestrogens and/or estrogens.This review provides a comprehensive and systematic literature search on phytoestrogens and its relationship with classical estrogen receptors and GPER-1 including its role in breast cancer, an issue still under discussion.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cell Transformation, Neoplastic; Dietary Exposure; Estrogen Antagonists; Female; Humans; Mammary Glands, Human; Phytoestrogens; Protective Factors; Receptors, Estrogen; Receptors, G-Protein-Coupled; Risk Assessment; Risk Factors; Signal Transduction

Phytoestrogens derived from plants exert estrogenic as well as antiestrogenic effects and multiple actions within breast cancer cells. Chemopreventive properties of phytoestrogens have emerged from epidemiological observations. In recent clinical research studies, phytoestrogens are safe and may even protect against breast cancer. In this brief review, the molecular mechanisms of phytoestrogens on regulation of cell cycle, apoptosis, estrogen receptors, cell signaling pathways, and epigenetic modulations in relation to breast cancer are discussed. Phytoestrogens have a preferential affinity for estrogen receptor (ER)-β, which appears to be associated with antiproliferative and anticarcinogenic effects. Moreover, while phytoestrogens not only inhibit ER-positive but also ER-negative breast cancer cells, the possibility of epigenetic modulation playing an important role is also discussed. In conclusion, as there are multiple targets and actions of phytoestrogens, extensive research is still necessary. However, due to low toxicity, low cost, and easy availability, their potent chemoprevention effects deserve further study.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast; Breast Neoplasms; Cell Proliferation; Epigenesis, Genetic; Female; Humans; Phytoestrogens; Receptors, Estrogen; Signal Transduction

Breast cancer is the most common cause of cancer mortality among women worldwide; therefore, a strategy to defeat breast cancer is an extremely important medical issue. One of the major challenges in this regard is multidrug resistance (MDR). Resveratrol, a well-known phytoestrogen, may be helpful as part of an overall strategy to defeat breast cancer. The mixed agonist and antagonist role of resveratrol for the estrogen receptor makes it a controversial but interesting molecule in cancer therapy, especially in hormone dependent cancers. Several in vitro investigations have suggested that resveratrol can reverse multidrug resistance. However, poor bioavailability of resveratrol is a potential limitation for resveratrol treatment and cancer outcome in vivo. Fortunately, combination therapy with other selected compounds improves resveratrol's bioavailability and/or a delay in its metabolism. This review summaries the available published literature dealing with the effects of resveratrol on multidrug resistance in cancer and more specifically, breast cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; DNA Repair; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estrogen Receptor Modulators; Female; Humans; Inactivation, Metabolic; Phytoestrogens; Resveratrol; Stilbenes

This review summarizes the 2016 NAMS/Pfizer-Wulf H. Utian Endowed Lecture that focused on the history and basic science of soy isoflavones. Described is a personal perspective of the background and history that led to the current interest in soy and isoflavones with a specific focus on the role that soy isoflavones play in the health of postmenopausal women. This overview covers the metabolism and physiological behavior of isoflavones, their biological properties that are of potential relevance to aging, issues related to the safety of soy isoflavones, and the role of the important intestinally derived metabolite S-(-)equol.

Topics: Animals; Breast Neoplasms; Diet; Female; Fermentation; Glycine max; Health Promotion; History, 20th Century; History, 21st Century; Humans; Intestinal Absorption; Isoflavones; Menopause; Microbiota; Phytoestrogens; Postmenopause; Soy Foods

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta-analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta-analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I

Topics: Breast Neoplasms; Cardiac Glycosides; Causality; Cohort Studies; Confidence Intervals; Confounding Factors, Epidemiologic; Estrogens; Female; Humans; Incidence; Models, Biological; Neoplasms, Hormone-Dependent; Observational Studies as Topic; Phytoestrogens; Registries; Risk Factors; Surveys and Questionnaires

In developed countries, women spend more than one-third of their life in the menopause and at least half of them experience vasomotor symptoms that impair their normal function and well-being. Long-term estrogen replacement therapy (HRT) with estrogen can suppress typical menopausal symptoms and prevents osteoporosis. When estrogen-only HRT is started within 10 years after the menopause, the prevalence of cardiovascular disease is reduced, mortality is lower, and the risk of breast cancer is not significantly increased. Postmenopausal genital and urinary problems with recurrent infections, incontinence, and dyspareunia can effectively be treated by vaginal application of estriol, which seems to be safe for women treated for breast cancer. HRT after the age of 60 years is associated with a lower number needed to treat than number needed to harm, implying that there would be one unfavorable side-effect for up to ten women experiencing a positive effect. However, further studies are needed regarding the risk-benefit ratio of HRT in women over 70 years. It is concluded that transdermal substitution therapy with estradiol may increase the number of quality-adjusted life years of postmenopausal women. The combination with nutriceutical food supplementation may add to this benefit, but complementary prospective trials are still needed.

Topics: Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Dyspareunia; Estradiol; Estriol; Estrogen Replacement Therapy; Female; Humans; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Postmenopause; Randomized Controlled Trials as Topic; Vagina

Worldwide, breast cancer is the most common malignant neoplasm and the second most common cause of cancer death in women. This malignancy is recognized to be estrogen-dependent and due to this feature, hormone replacement therapy is regarded as potentially dangerous in breast cancer survivors who seek relief of their menopausal symptoms. Whereas hot flashes are detected in nearly half of postmenopausal women with a relatively high frequency and severity, botanic sources of estrogens have been proposed as an alternative treatment. Nevertheless, estrogenic properties of these compounds suggest possibility of stimulating cancer recurrence or worsening prognosis in survivors. As well, effects in improving vasomotor climacteric changes is controversial. Many studies have considered the subject, some focusing on efficacy of phytoestrogens for control of menopausal symptoms, and others discussing effects of these compounds on breast cancer outcome in terms of survival or recurrence. The present article is a concise review of the effects of consumption of phytoestrogens on menopausal symptoms, namely hot flashes, and breast cancer recurrence and mortality in survivors of the disease. Overall, the major part of the current existing literature is in favor of positive effects of phytoestrogens on breast cancer prognosis, but the efficacy on menopausal symptoms is probably minimal at the best.

Topics: Breast Neoplasms; Female; Hot Flashes; Humans; Menopause; Phytoestrogens

All the currently available cancer therapeutic options are expensive but none of them are safe. However, traditional plant-derived medicines or compounds are relatively safe. One widely known such compound is beta-sitosterol (BS), a plant derived nutrient with anticancer properties against breast cancer, prostate cancer, colon cancer, lung cancer, stomach cancer, ovarian cancer, and leukemia. Studies have shown that BS interfere with multiple cell signaling pathways, including cell cycle, apoptosis, proliferation, survival, invasion, angiogenesis, metastasis and inflammation. Most of the studies are incomplete partly due to the fact that BS is relatively less potent. But the fact that it is generally considered as nontoxic, the opposite of all currently available cancer chemo-therapeutics, is missed by almost all research communities. To offset the lower efficacy of BS, designing BS delivery for "cancer cell specific" therapy hold huge potential. Delivery of BS through liposome is one of such demonstrations that has shown to be highly promising. But further research did not progress neither in the field of drug delivery of BS nor in the field on how BS mediated anticancer activities could be improved, thus making BS an orphan nutraceutical. Therefore, extensive research with BS as potent anticancer nutraceutical is highly recommended.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Colonic Neoplasms; Dietary Supplements; Drug Delivery Systems; Female; Humans; Leukemia; Liposomes; Lung Neoplasms; Male; Neoplasms; Orphan Drug Production; Phytoestrogens; Prostatic Neoplasms; Signal Transduction; Sitosterols

The heritable component of breast cancer accounts for only a small proportion of total incidences. Environmental and lifestyle factors are therefore considered to among the major influencing components increasing breast cancer risk. Endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment. The estrogenic property of EDCs has thus shown many associations between ongoing exposures and the development of endocrine-related diseases, including breast cancer. The environment consists of a heterogenous population of EDCs and despite many identified modes of action, including that of altering the epigenome, drawing definitive correlations regarding breast cancer has been a point of much discussion. In this review, we describe in detail well-characterized EDCs and their actions in the environment, their ability to disrupt mammary gland formation in animal and human experimental models and their associations with exposure and breast cancer risk. We also highlight the susceptibility of early-life exposure to each EDC to mediate epigenetic alterations, and where possible describe how these epigenome changes influence breast cancer risk.

Topics: Animals; Breast Neoplasms; Endocrine Disruptors; Environmental Pollutants; Epigenesis, Genetic; Female; Genome; Humans; Life Style; Phytoestrogens

Menopause is characterized by an altered hormonal status and by a decrease in life quality due to the appearance of uncomfortable symptoms. Nowadays, with increasing life span, women spend one-third of their lifetime under menopause. Understanding menopause-associated pathophysiology and developing new strategies to improve the treatment of menopausal-associated symptoms is an important topic in the clinic. This review describes physiological and hormone alterations observed during menopause and therapeutic strategies used during this period. We critically address the benefits and doubts associated with estrogen/progesterone-based hormone replacement therapy (HRT) and discuss the use of phytoestrogens (PEs) as a possible alternative. These relevant plant-derived compounds have structural similarities to estradiol, interacting with cell proteins and organelles, presenting several advantages and disadvantages versus traditional HRT in the context of menopause. However, a better assessment of PEs safety/efficacy would warrant a possible widespread clinical use.

Topics: Breast Neoplasms; Female; Hormone Replacement Therapy; Humans; Menopause; Phytoestrogens

Phytoestrogens were originally identified as compounds having a close similarity in structure to estrogens and harboring weak estrogen activity. The interest in phytoestrogens as potential therapeutic agents has recently risen in the field of oncology, since population based studies have linked phytoestrogens consumption with a decreased risk of mortality due to several types of cancer. This review departs from the main focus of these articles by describing recent advances in our understanding of phytoestrogen potential action on mitochondria, specifically on mitochondrial biogenesis, dynamics and functionality, as well as mitoptosis in breast cancer. Further studies are necessary to explain the effects of individual phytoestrogens on mitochondrial biogenesis and dynamics and for designing of new therapy targets for cancer treatment, nevertheless area promising therapeutic approach.

Topics: Animals; Breast Neoplasms; Energy Metabolism; Female; Humans; Mitochondria; Phytoestrogens; Receptors, Estrogen

Flaxseed (FS), rich in the phytoestrogen lignans and α-linolenic acid-rich oil, has been suggested to have an anticancer effect. Questions remain whether FS and its lignan and oil components are effective in reducing breast cancer risk and tumour growth, and can interact beneficially with breast cancer drugs. To find answers, in vitro, animal, observational, and clinical studies on FS and its lignan and oil components were reviewed. The majority of studies in various rodent models show that 2.5%-10% FS diet or the equivalent amount of lignan or oil reduces tumour growth. Ten percent FS and equivalent lignans do not interfere with but rather increase the effectiveness of tamoxifen (80 mg/day) while the 4% FS oil increases trastuzumab/Herceptin (2.5 mg/kg) effectiveness. Observational studies show that FS and lignan intake, urinary excretion, or serum levels are associated with reduced risk, particularly in postmenopausal women. Lignans reduce breast cancer and all-cause mortality by 33%-70% and 40%-53%, respectively, without reducing tamoxifen effectiveness. Clinical trials show that FS (25 g/day with 50 mg lignans; 32 days) reduces tumour growth in breast cancer patients and lignans (50 mg/day; 1 year) reduces risk in premenopausal women. Mechanisms include decreased cell proliferation and angiogenesis and increased apoptosis through modulation of estrogen metabolism and estrogen receptor and growth factor receptor signalling pathways. More clinical trials are needed but current overall evidence indicates that FS and its components are effective in the risk reduction and treatment of breast cancer and safe for consumption by breast cancer patients.

Topics: alpha-Linolenic Acid; Animals; Antineoplastic Agents; Breast Neoplasms; Disease Models, Animal; Drug Interactions; Female; Flax; Humans; Lignans; Phytoestrogens; Risk Factors

Flavonoids are a large group of ubiquitous polyphenolic secondary metabolites in plants with a wide range of properties, including a widely reported anti-cancer effect. The present review focuses on the different known mechanisms partaking in said anti-tumour effects, with particular emphasis on breast cancer. Their structure and reactivity allows flavonoids to work as antioxidant agents and phyto-oestrogens, modulating oestrogen signalling and metabolism to induce an overall anti-proliferative response. Other effects include the ability of flavonoids to modulate the CYP1 (cytochrome P450 1) and ABC (ATP-binding cassette) protein families, involved in carcinogenesis and drug delivery respectively. They can also induce apoptosis and cell cycle arrest and regulate other signalling pathways involved in the development and progression of cancer. In conclusion, there is accumulating evidence on the versatility of flavonoids and the numerous activities contributing to their anti-tumour effect. The complex, yet effective, mechanism of action of flavonoids, together with their interesting pharmacological properties, is the basis for their potential application in breast and other cancers. This rationale has led to the current interest in the application of flavonoids, including clinical trials currently underway and the development of novel flavonoids with improved properties, which hold great promise for tackling breast cancer.

Topics: Antineoplastic Agents; Antioxidants; Breast Neoplasms; Female; Flavonoids; Humans; Phytoestrogens

The chemical structure, classification, source, metabolism, physiological and health effects of plant phytoestrogens and mechanisms of their action are reviewed. The available knowledge suggests that phytoestrogens can affect a number of physiological and pathological processes related to reproduction, bone remodeling, skin, cardiovascular, nervous, immune systems and metabolism. Due to these effects, phytoestrogens and phytoestrogen-containing diet can be useful for the prevention and treatment of menopausal symptoms, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and metabolic diseases. Possible problems in understanding and application of phytoestrogens (multiple targets and multiple estrogen receptor -dependent and -independent mechanisms of action, the discrepancy between the results of experimental and clinical studies, adequate source of phytoestrogen) have been discussed.

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Female; Humans; Osteoporosis; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Treatment Outcome

Phytoestrogens are natural endocrine disruptors that interfere with estrogenic pathways. They insert directly within the hormone-binding domain of ERα and β, with a preference for the β isoform of which the concentration predominates in the normal mammary epithelium. Since ERβ antagonizes the growth promoting effect of ERα, which is mainly expressed in estrogen-sensitive tumor cells, a potential protective action against breast cancer incidence has been ascribed to phytoestrogens. The fact that Asian women living in far-east countries who consume isoflavone-rich food are less subjected to breast cancer emergence than their congeners in the USA as well as Caucasian women has been advocated to justify such a concept. Overview of data concerning the mechanism of action phytoestrogens reveals that such a view is an oversimplification: Such compounds interfere with a huge panel of regulatory proteins, giving rise to both promoting and antagonizing carcinogenic effects. Moreover, various physiological and pathological factors able to amplify these effects are not often sufficiently taken into account, which increases the difficulty to interpret data. Nevertheless, this overview of data established that chemical structures and concentrations modulate such effects: at the micromolar level, isoflavones activate ERα-mediated transcription and breast cancer cell proliferation while flavones fail to induce any significant promoting effects. At higher doses, both classes of compounds may display an antitumor activity. Reasons for such distinct behaviors as well as their potential impact in therapeutic applications are analyzed here. Ability of isoflavones and flavones to antagonize the association of calmodulin to ERα, which is required for its enhanced transcriptional activity is evoked to justify the antitumor activity ascribed to some flavones. Finally, a suspicion that peculiar classes of phytoestrogens may adopt a SERM-like conformation is addressed in a context of selection and synthesis of compounds with non-equivocal therapeutic value. This article is part of a Special Issue entitled "Phytoestrogens".

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Binding Sites; Breast Neoplasms; Clinical Trials as Topic; Female; Guidelines as Topic; Humans; Isoflavones; Phytoestrogens; Protein Binding; Receptors, Estrogen

Breast cancer risk has both heritable and environment/lifestyle components. The heritable component is a small contribution (5-27 %), leaving the majority of risk to environment (e.g., applied chemicals, food residues, occupational hazards, pharmaceuticals, stress) and lifestyle (e.g., physical activity, cosmetics, water source, alcohol, smoking). However, these factors are not well-defined, primarily due to the enormous number of factors to be considered. In both humans and rodent models, environmental factors that act as endocrine disrupting compounds (EDCs) have been shown to disrupt normal mammary development and lead to adverse lifelong consequences, especially when exposures occur during early life. EDCs can act directly or indirectly on mammary tissue to increase sensitivity to chemical carcinogens or enhance development of hyperplasia, beaded ducts, or tumors. Protective effects have also been reported. The mechanisms for these changes are not well understood. Environmental agents may also act as carcinogens in adult rodent models, directly causing or promoting tumor development, typically in more than one organ. Many of the environmental agents that act as EDCs and are known to affect the breast are discussed. Understanding the mechanism(s) of action for these compounds will be critical to prevent their effects on the breast in the future.

Topics: Aging; Animals; Anticarcinogenic Agents; Breast Neoplasms; Disease Susceptibility; Endocrine Disruptors; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Phytoestrogens

Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer death among women. Soy isoflavones have been widely studied and among all isoflavones equol has been gaining interest with regard to its relationship with breast cancer risk. Obesity has been revealed as one of the breast cancer risk factors, known to be associated with high levels of circulating insulin and decreased levels of adiponectin. Hence there have been many studies investigating relationships between insulin and adiponectin levels and breast cancer risk. Additionally recent findings have suggested that insulin and adiponectin themselves may have influence on breast cancer development, independent of obesity. In the present review, we discuss the relationships between breast cancer risk and equol, insulin and adiponectin levels, which are three important factors in our ongoing hospital-based case-control study. Herein these factors are reviewed not only from the clinical viewpoint but also from possible chemical and biological points of view which may explain clinical observations.

Topics: Adiponectin; Breast Neoplasms; Case-Control Studies; Equol; Female; Humans; Hypoglycemic Agents; Insulin; Obesity; Phytoestrogens; Risk Factors

Epidemiological and migratory evidence suggests that dietary soy consumption can lower the risk for breast cancer. The role of soy isoflavones in cancer prevention and promotion is somewhat unclear. There are two views in terms of soy isoflavones and breast cancer. One line of evidence suggests that soy and its isoflavones have exhibited cancer-preventive properties including lengthening the menstrual cycle, altering estrogen metabolism away from cancerous compounds, and demonstrating anti-proliferative properties in vivo. On the contrary, isoflavones found in soy products are suggested to behave as weak estrogens and as such, much speculation surrounds the influence of soy and/or its isoflavones on hormone-receptor-positive cancers. The objective of this review is to present the latest knowledge regarding the role of soy and its isoflavones with the development and advancement of breast cancer, the safety of soy isoflavones for breast cancer survivors, and a comparison of the carcinogenic effects in animal models following soy isoflavone and estrogen administration. This review compares and contrasts literature in terms of the anti-cancer and cancer-promoting effects of soy isoflavones and estrogen in humans and animal models. In conclusion, current human and animal data provide evidence for several anticancer properties of soy and/or its isoflavones. Although the specific quantities and constituents responsible for the observed anti-cancer effects have not been elucidated, it appears that soy isoflavones do not function as an estrogen, but rather exhibit anti-estrogenic properties. However, their metabolism differs between humans and animals and therefore the outcomes of animal studies may not be applicable to humans. The majority of breast cancer cases are hormone-receptor-positive; therefore, soy isoflavones should be considered a potential anti-cancer therapeutic agent and warrant further investigation.

Topics: Animals; Asian People; Breast Neoplasms; Estrogens; Female; Glycine max; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Phytoestrogens; White People

Breast cancer is the most occurring type of cancer among women. In Slovakia, there are yearly diagnosed about 1900 new cases of this disease. Breast cancer treatment is very expensive, psychic stressful and in some cases ineffective. Therefore, it is essential to search for new and/or alternative methods for breast cancer treatment, since nuclear receptors are considered to be a central goal for maximizing treatment opportunities in breast cancer. Among natural ligands for estrogen receptors (ERα and ERβ), which are member of nuclear receptors superfamily, belongs also isoflavones. These natural compounds have similar structure to main female hormon-17β estradiol. A rich source of isoflavones is soy and its products. Three aglycones form of isoflavones (genistein, daidzein, glycitein) are predominantly found in soybean and red clover. Among other important isoflavones belongs also biochanin A and formononetin.

Topics: Animals; Breast Neoplasms; Humans; Isoflavones; Molecular Targeted Therapy; Phytoestrogens; Receptors, Cytoplasmic and Nuclear

The impact of soyfood intake on breast cancer risk has been intensely investigated. This focus can be attributed to soyfoods being uniquely rich dietary sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor (ER) modulators. The finding that dietary genistein, the primary soybean isoflavone, stimulates the growth of existing mammary tumors in ovariectomized athymic mice implanted with ER-positive breast cancer cells has led many oncologists to advise their patients against the use of soyfoods. However, the clinical evidence indicates that isoflavone exposure has little effect on markers of breast cancer risk. Furthermore, a pooled analysis that involved 9,514 breast cancer survivors found higher isoflavone intake was associated with a statistically significant 25% reduction in recurrence over the average 7.4-year follow-up period. Given the clinical and epidemiologic data, our position is that clinicians should allow soyfood use by patients for whom soyfoods already represent a normal part of their diet, and should not discourage other breast cancer survivors from moderate consumption.

Topics: Animals; Breast Neoplasms; Cell Cycle; Cell Proliferation; Diet; Epithelial Cells; Female; Genistein; Hormones; Humans; Isoflavones; Mammography; MCF-7 Cells; Mice; Nipples; Phytoestrogens; Soy Foods

Digoxin, a phyto-estrogen, binds with estrogen receptors (ER) and can cause gynecomastia. Among women currently using digoxin, breast and uterus cancer incidences are significantly increased (approximate risk ratios, 1.3-1.5). Both cancers are often estrogen sensitive. In contrast, ovary and cervix cancers are relatively estrogen insensitive, and incidence is unaffected by digoxin exposure. When digoxin use stops, incidence rapidly reverts to that in nonusers. These patterns parallel those of estrogen, suggesting that digoxin works via ER-stimulated proliferation of ductal and/or acinar cells, accelerating the growth of nascent cancers. Also consistent with an estrogenic effect, men using digoxin have a small but significant reduction in prostate cancer (risk ratio, 0.76). Other estrogen-like drugs, particularly spironolactone, should be investigated for similar effects. The effect of digoxin use in women being treated for breast cancer or in survivors is unknown. Women with estrogen-sensitive cancers on adjuvant therapy may take tamoxifen, which blocks ERs. However, postmenopausal patients may use aromatase inhibitors, which block estrogen production while leaving ERs susceptible to digoxin. If adverse effects are found, tamoxifen may be preferred over aromatase inhibitors in patients receiving estrogen-mimicking drugs. Alternatively, other cardiotropic drugs might be considered in women with or at high risk of developing estrogen-sensitive cancers.

Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Digoxin; Estrogens; Female; Humans; Male; Neoplasms, Hormone-Dependent; Phytoestrogens; Receptors, Estrogen; Risk Factors; Selective Estrogen Receptor Modulators; Spironolactone; Tamoxifen; Uterine Neoplasms

To review the evidence that isoflavones are effective treatments for menopausal symptoms and to present the safety data.. The databases Scopus, ScienceDirect and Primo Central Index were searched and preference was given to systematic reviews and meta-analyses.. The available evidence suggests that isoflavones do not relieve menopausal vasomotor symptoms any better than placebo. Long-term safety studies suggest that women who consume a diet high in isoflavones may have a lower risk of endometrial and ovarian cancer.. Isoflavones cannot be recommended for the relief of hot flushes.

Topics: Breast Neoplasms; Female; Hot Flashes; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Risk Factors

Breast cancer is one of the most common types of cancer in women, and is the second leading cause of cancer-related deaths in the United States. Chemoprevention using phytoestrogens (PEs) for breast cancer may be a valid strategy. PEs are phytochemicals with estrogen-like structures and can be classified into four types: isoflavones, lignans, stilbenes and coumestans. They are widely distributed in diet and herbs and have shown anti-cancer activity via mechanisms including estrogen receptor modulation, aromatase inhibition, and anti-angiogenesis. Genistein, daidzein and resveratrol are some of the most studied PE examples. Quality control in product manufacturing and clinical study design is a critical issue in developing them as clinically effective chemopreventive agents for breast cancer.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Clinical Trials as Topic; Drug Discovery; Estrogen Receptor Modulators; Female; Humans; Molecular Structure; Phytoestrogens

Accumulated exposure to high levels of estrogen is associated with an increased incidence of breast cancer. Thus, factors such as early puberty, late menopause and hormone replacement therapy are considered to be risk factors, whereas early childbirth, breastfeeding and puberty at a later age are known to consistently decrease the lifetime breast cancer risk. Epidemiological studies suggest that consumption of isoflavones correlates with a lower incidence of breast cancer. Data from human intervention studies show that the effects of isoflavones on early breast cancer markers differ between pre- and post-menopausal women. The reports from experimental animals (rats and mice) on mammary tumors are variable. These results taken together with heterogeneous outcomes of human interventions, have led to a controversy surrounding the intake of isoflavones to reduce breast cancer risk. This review summarizes recent studies and analyzes factors that could explain the variability of results. In mammary tissue, from the cellular endocrine viewpoint, we analyze the effect of isoflavones on the estrogen receptor and their capacity to act as agonists or antagonists. On the issue of puberty timing, we analyze the mechanisms by which girls, but not boys, with higher prepuberal isoflavone intakes appear to enter puberty at a later age.

Topics: Animals; Breast Neoplasms; Female; Humans; Isoflavones; Male; Mice; Phytoestrogens; Puberty; Rats; Receptors, Estrogen; Risk Factors; Soy Foods

Phytoestrogens are a group of non-steroidal compounds of plant origin that present structural and functional similarities with estradiol. Isoflavones are their most widely known category. There are different mechanisms of action of isoflavones accepted, although they may be considered as selective modulators of estrogen receptors. On the other hand, Cimicifuga Racemosa is a perennial plant used traditionally for problems related to menstruation. Its action mechanisms have not been totally identified. There is a growing interest in the usefulness of phytotherapy in the treatment of symptoms and menopause-related diseases. Isoflavones and Cimicifuga Racemosa moderately improve vasomotor symptoms in menopausal women, particularly in those who have a greater number of hot flushes. Furthermore, trials performed with soy isoflavones have observed a reduction of the loss of bone mineral density in postmenopausal women and a slight decrease in LDL cholesterol. In short, phytotherapy will constitute a therapeutic option that can offer assistance to women who want to improve their quality of life through relief of vasomotor symptoms or benefit from other effects for their health.

Topics: Bone Density; Breast Neoplasms; Cimicifuga; Endometrium; Estrogen Replacement Therapy; Female; Humans; Isoflavones; Menopause; Phytoestrogens; Phytotherapy; Plant Extracts; Risk Factors; Vasomotor System

Diet is thought to account for about 25% of cancers in developed countries. It is well documented that the risks associated with both the breast cancer itself and its treatments are important for women previously treated for breast cancer. Women are at risk of recurrence of the primary disease and prone to develop treatment-induced co-morbidities, some of which are thought to be modified by diet. With a view to making dietary recommendations for the breast cancer patients we encounter in our clinical nursing research, we mined the literature to scope the most current robust evidence concerning the role of the diet in protecting women against the recurrence of breast cancer and its potential to ameliorate some of the longer-term morbidities associated with the disease. We found that the evidence about the role of the diet in breast cancer recurrence is largely inconclusive. However, drawing on international guidelines enabled us to make three definitive recommendations: women at risk of breast cancer recurrence, or who experience co-morbidities as a result of treatment, should limit their exposure to alcohol, moderate their nutritional intake so it does not contribute to post-menopausal weight gain, and should adhere to a balanced diet. Nursing education planned for breast cancer patients about dietary issues should ideally be individually tailored, based on a good understanding of the international recommendations and the evidence underpinning them.

Topics: Breast Neoplasms; Chronic Disease; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Female; Health Behavior; Humans; Micronutrients; Neoplasm Recurrence, Local; Oncology Nursing; Patient Education as Topic; Phytoestrogens

Aromatase, the key enzyme in estrogen biosynthesis, converts androstenedione to estrone and testosterone to estradiol. The enzyme is expressed in various tissues such as ovary, placenta, bone, brain, skin, and adipose tissue. Aromatase enzyme is encoded by a single gene CYP 19A1 and its expression is controlled by tissue-specific promoters. Aromatase mRNA is primarily transcribed from promoter I.4 in normal breast tissue and physiological levels of aromatase are found in breast adipose stromal fibroblasts. Under the conditions of breast cancer, as a result of the activation of a distinct set of aromatase promoters (I.3, II, and I.7) aromatase expression is enhanced leading to local overproduction of estrogen that promotes breast cancer. Aromatase is considered as a potential target for endocrine treatment of breast cancer but due to nonspecific reduction of aromatase activity in other tissues, aromatase inhibitors (AIs) are associated with undesirable side effects such as bone loss, and abnormal lipid metabolism. Inhibition of aromatase expression by inactivating breast tumor-specific aromatase promoters can selectively block estrogen production at the tumor site. Although several synthetic chemical compounds and nuclear receptor ligands are known to inhibit the activity of the tumor-specific aromatase promoters, further development of more specific and efficacious drugs without adverse effects is still warranted. Plants are rich in chemopreventive agents that have a great potential to be used in chemotherapy for hormone dependent breast cancer which could serve as a source for natural AIs. In this brief review, we summarize the studies on phytochemicals such as biochanin A, genistein, quercetin, isoliquiritigenin, resveratrol, and grape seed extracts related to their effect on the activation of breast cancer-associated aromatase promoters and discuss their aromatase inhibitory potential to be used as safer chemotherapeutic agents for specific hormone-dependent breast cancer.

Topics: Aromatase; Aromatase Inhibitors; Biological Products; Breast Neoplasms; Estrogens; Female; Humans; Neoplasms, Hormone-Dependent; Phytoestrogens; Pregnancy; Promoter Regions, Genetic

Changes in the regulation of potassium channels are increasingly implicated in the altered activity of breast cancer cells. Increased or reduced expression of a number of K(+) channels have been identified in numerous breast cancer cell lines and cancerous tissue biopsy samples, compared to normal tissue, and are associated with tumor formation and spread, enhanced levels of proliferation, and resistance to apoptotic stimuli. Through knockout or silencing of K(+) channel genes, and use of specific or more broad pharmacologic K(+) channel blockers, the growth of numerous cell lines, including breast cancer cells, has been modified. In this manner it has been proposed that in MCF7 breast cancer cells proliferation appears to be regulated by the activity of a number of K(+) channels, including the Ca(2+) activated K(+) channels, and the voltage-gated K(+) channels hEAG and K(v)1.1. The effect of phytoestrogens on K(+) channels has not been extensively studied but yields some interesting results. In a number of cell lines the phytoestrogen genistein inhibits K(+) current through several channels including K(v)1.3 and hERG. Where it has been used, structurally similar daidzein has little or no effect on K(+) channel activity. Since many K(+) channels have roles in proliferation and apoptosis in breast cancer cells, the impact of K(+) channel regulation by phytoestrogens is of potentially great relevance.

Topics: Breast Neoplasms; Cell Line, Tumor; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Potassium Channels

The increased risk of breast cancer recently observed with some specific estro-progestin associations has raised concerns about the harmful effects of menopausal hormone replacement therapy (HRT). It has been proposed that phytoestrogens (PEs), which have a similar chemical structure to estrogens, could be used as HRT. The main selling points of these preparations concern the management of hot flashes and their potential beneficial effects on breast tissue. In this review, we will address the effects of PE on hot flashes and breast cancer risk as well as the questions raised on a chemical point of view. We conclude that the efficacy of a PE rich diet or nutritional supplements is not clearly established. The use of PE as an alternative for HRT cannot be advocated for now, due to insufficient and conflicting data on efficacy and safety. Moreover, due to the hormone dependence of breast cancer, PE use must be contraindicated in breast cancer survivors.

Topics: Breast Neoplasms; Contraindications; Diet; Female; Hot Flashes; Humans; Phytoestrogens; Phytotherapy; Plant Extracts; Plants; Risk

The present work reviews recent findings related to the action of steroidal (physiological) estrogens on normal mammary gland development and carcinogenesis, as well as effects of related environmental mediators (phyto- and xeno-estrogens), the role of which remains controversial. Orchestration by estrogen receptors (i.e. ERα and ERβ) and coregulators of growth, apoptosis and differentiation of epithelial cells, directed our analysis. The bidirectional coordination between epithelium and stroma in parallel with maintenance of stemness are also investigated. The relevance of nuclear and extranuclear localization of ERs and other eventual estrogen binding sites, mediating differential actions in regard to these various topics, is critically addressed to delineate the importance of direct and indirect activation procedures and delicate feedback loops (ligand-induced or/and cross-talk activation, respectively). The inclusion of the outlined regulatory concepts in drug design programs for the prevention and treatment of breast cancer may have potent effects.

Topics: Animals; Breast; Breast Neoplasms; Carcinogens, Environmental; Environmental Pollutants; Estradiol Congeners; Estrogens; Female; Humans; Isoflavones; Mammary Glands, Animal; Mice; Models, Biological; Phytoestrogens; Receptor Cross-Talk; Receptors, Estrogen; Signal Transduction; Stem Cells

There are important safety concerns associated with dietary supplements and foods rich in phytoestrogens, especially for breast cancer patients with hormone-sensitive disease. However, no consensus has been reached concerning specific dietary items that should be avoided, and safe levels of potentially problematic foods have yet to be determined. Excellent qualitative reviews of phytoestrogens and breast cancer have been published. These list agents that contain phytoestrogens and offer general cautions. Quantitative reviews, however, are needed but not yet available. Here we review quantitative data on phytoestrogens, their interaction with estrogen receptors, their bioavailability and pharmacokinetics, and their effects on breast cancer cells and animal models. We also note foods and botanicals with substances that interact with estrogen receptors and discuss the phytoestrogens they contain. Based on current evidence, we propose recommendations for advising breast cancer patients, which may also serve as a basis for the development of clinical practice guidelines.

Topics: Animals; Breast Neoplasms; Dietary Supplements; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Soy Foods

To review and summarise current evidence on the efficacy and safety of herbal medicinal products for the relief of hot flushes in women with previous breast cancer.. A literature search was conducted in the databases of Medline, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), PSYCHINFO, AMED (Allied and Complementary Medicine), NCCAM (The National Centre for Complementary and Alternative Medicine).. Black cohosh and phytoestrogens have received the most research attention but there is currently insufficient evidence to recommend either for relief of flushes. Black cohosh use appears safe in women with previous breast cancer. Opposing advice has been given regarding the safety of dietary phytoestrogen use for women with previous breast cancer, but there is emerging data that soyfood phytoestrogen intake may have a beneficial effect on tumour recurrence.. The majority of studies, regarding the efficacy of herbal treatments for hot flushes, have not been conducted in women with breast cancer and many are of short duration. Increased pharmacovigilance practices for herbal medicines are required with initiatives to stimulate reporting of suspected adverse reactions.

Topics: Actaea; Animals; Breast Neoplasms; Cimicifuga; Diet; Female; Glycine max; Herb-Drug Interactions; Hot Flashes; Humans; Phytoestrogens; Phytotherapy; Plant Preparations

Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens.

Topics: Animals; Brain; Breast Neoplasms; Diethylstilbestrol; Endocrine Disruptors; Female; Genitalia; Heart Diseases; Humans; Male; Menopause; Menstrual Cycle; Mice; Osteoporosis; Phytoestrogens; Puberty; Rats; Sexual Behavior; Soybean Proteins

Many environmental compounds with oestrogenic activity are measurable in the human breast and oestrogen is a known factor in breast cancer development. Exposure to environmental oestrogens occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable oestrogenic responses. Results presented here and elsewhere demonstrate that in combination, chemicals can give oestrogenic responses at lower concentrations, which suggests that in the breast, low doses of many compounds could sum to give a significant oestrogenic stimulus. Updated incidence figures show a continued disproportionate incidence of breast cancer in Britain in the upper outer quadrant of the breast which is also the region to which multiple cosmetic chemicals are applied.. If exposure to complex mixtures of oestrogenic chemicals in consumer products is a factor in breast cancer development, then a strategy for breast cancer prevention could become possible.

Topics: Animals; Breast Neoplasms; Cosmetics; Environmental Exposure; Estrogens; Household Products; Humans; Hydrocarbons, Chlorinated; Phytoestrogens

The use of phytoestrogens for various perceived health benefits is widespread. Despite 20 years of research the evidence for any significant health benefits remains inconclusive. Pre clinical trials have demonstrated both non-genomic and genomic actions of constituents of phytoestrogens including selective, but weak, binding to estrogen receptors, with a preference for ER B over ER A. Evidence of clinically relevant biological effects from observational studies and randomized trials has, in general, been lacking. Despite many trials there remains little evidence that phytoestrogens, whether dietary or supplemented, significantly relieve menopausal vasomotor symptoms or cognition. Several potential mechanisms for a positive effect on bone and cardiovascular health have been demonstrated however no fracture prevention data or cardiovascular end point benefit has yet been demonstrated. In vitro effects of phytoestrogens on breast cells have been both stimulatory and inhibitory however net effects appear neutral with observational studies finding no change in breast cancer risk. No effect has been seen on endometrial or other cancers and side effect profiles have, in general, been mild.

Topics: Animals; Bone Density; Breast Neoplasms; Cardiovascular Diseases; Cardiovascular System; Female; Humans; Menopause; Phytoestrogens; Phytotherapy; Plant Extracts; Receptors, Estrogen

Phytoestrogens are polyphenolic secondary plant metabolites that have structural and functional similarities to 17beta-oestradiol and have been associated with a protective effect against hormone-related cancers. Most foods in the UK only contain small amounts of phytoestrogens (median content 21 microg/100 g) and the highest content is found in soya and soya-containing foods. The highest phytoestrogen content in commonly consumed foods is found in breads (average content 450 microg/100 g), the main source of isoflavones in the UK diet. The phytoestrogen consumption in cases and controls was considerably lower than in Asian countries. No significant associations between phytoestrogen intake and breast cancer risk in a nested case-control study in EPIC Norfolk were found. Conversely, colorectal cancer risk was inversely associated with enterolignan intake in women but not in men. Prostate cancer risk was positively associated with enterolignan intake, however this association became non-significant when adjusting for dairy intake, suggesting that enterolignans can act as a surrogate marker for dairy or calcium intake.

Topics: Aged; Animals; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Food Analysis; Humans; Isoflavones; Lignans; Male; Middle Aged; Phytoestrogens; Prostatic Neoplasms; Risk Factors; United Kingdom

Breast cancer (BC) is a polygenic and multifactorial disease for which estrogens have been recognized as the main risk factor, and for which lifestyle plays a key role. Previous epidemiologic cancer research performed in Uruguayan population delimited its dietary and anthropometric profiles. Recognizing the difficulty for universalizing a nutritional basis for prevention due to different eating patterns among regions and countries, we summarize the existent knowledge linking nutrition, estrogens, metabolism and BC. As an attempt towards primary prevention of BC, we present recommendations mainly based on country-specific research findings and modifiable putative risk and protective factors, proposing to modify the intake of meats and other fatty foods--especially sources of Ω-6 and Ω-3 fatty acids--adding olive oil, selected vegetables, citrus fruits and working towards adequate body fat/muscle proportions. From a medical and ethical viewpoint, it is justified to recommend certain nutritional changes to women, because no adverse side effects are expected to occur.

Topics: Anthropometry; Breast Neoplasms; Carotenoids; Cholesterol; Diet; Dietary Fats; Estrogens; Feeding Behavior; Female; Food; Humans; Meat; Phytoestrogens; Primary Prevention; Risk Factors; Uruguay; Vegetables; Vitamin D

The increased interest in phytoestrogens in the management of menopausal symptoms followed the publication of the Women's Health Initiative study. A wide-spread perception that these plant-derived compounds are equivalent to estrogen was established. These compounds evolved to fulfill the needs of plant physiological processes and are natural for the plant cells but not natural to the human cell. Epidemiological data suggest a possible protective effect of phytoestrogen if consumed during adolescence, but later on in life this effect is not clear. The utility of phytoestrogen as a "natural and safe" alternative to estrogen in alleviating vasomotor symptoms has failed the test in randomized clinical trials. Because many breast cancer sufferers seek in phytoestrogen a relief of estrogen deficiency symptoms, the possible interaction of such remedies with risk of recurrence of breast cancer or interference with tamoxifen action should not be overlooked.

Topics: Breast; Breast Neoplasms; Climacteric; Female; Humans; Medicine; Phytoestrogens; Recurrence; Treatment Outcome

Lignans found in plant foods are converted by the intestinal microflora to enterolignans. The structure of enterolignans is similar to that of estrogens, which has inspired researchers to examine a potential protective association in relation to health outcomes. Numerous epidemiological studies have measured concentration of enterolignans, mainly enterolactone, in blood or urine as a biomarker of lignan exposure and studied its relation to breast cancer risk. Case-control studies have shown decreased breast cancer risk associated with high circulating enterolactone concentrations, but results demonstrated by prospective cohort studies are less clear. The purpose of this review is to discuss factors that may contribute to these contradictory findings obtained in epidemiological studies, including age distribution, enterolactone measurement error, heterogeneity of breast cancer subtypes, and genetic factors. Different sources of enterolactone precursors may also contribute to inconclusive results. In conclusion, to get robust evidence of the health effects of lignans and enterolactone, more effort has to be put on methodological problems, including reducing measurement errors in enterolactone estimation, and to identify factors that modify the effect.

Topics: Biomarkers; Breast Neoplasms; Epidemiologic Methods; Female; Humans; Lignans; Phytoestrogens; Phytotherapy

Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.

Topics: Animals; Breast Neoplasms; Endocrine Disruptors; Glycine max; Humans; Infant Formula; Phytoestrogens; Puberty, Precocious; Reproduction

Side effects and contraindications connected with hormonal replacement therapy in climacterium resulted in search for new methods of softening menopausal symptoms. The aim of the following study was to evaluate, based on literature analysis, the effectiveness of phytohormonal therapy as an alternative method of relieving the symptoms of menopausal period and preventing the diseases connected with deficiency of estrogens after menopause. Phytoestrogens therapy reduces the number and strength of the vasomotor symptoms and improves serum lipid profile. Moreover phytoestrogens show beneficial effects on bone tissue metabolism, skin and mucous membranes condition and are applicable in chemoprevention. This therapy is an effective method, allowing to avoid further changes in blood and urogenital systems, which result from estrogen stimulation deficiency. Phytoestrogens administration is an efficient method of relieving postmenopausal symptoms, facilitating the difficult menopausal period and keeping good health condition.

Topics: Breast Neoplasms; Cardiovascular Diseases; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Isoflavones; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; Phytotherapy; Postmenopause; Women's Health

Breast cancer is the most common female cancer in Western Europe and North America, and becoming an increasing problem in developing countries such as India and China. We review recent studies (published 1 January 2007-31 August 2008) on the impact of diet on breast cancer risk.. Recent studies have focused on the controversial association for dietary fat and breast cancer as well as the role of newer aspects such as glycemic index, dietary patterns and diet-gene interactions. Evidence that some of the associations may be modified by oestrogen and progesterone receptor status has been presented. Still, only alcohol intake, being overweight and weight gain have shown consistent and strong positive associations with breast cancer risk. The reasons for the null or weak associations often observed regarding diet and breast cancer might be several. For example, there may be no causal association, or existing associations may be masked by measurement error, timing of dietary exposure and differences according to tumour characteristics or diet-gene interactions.. Numerous epidemiological studies on diet and breast cancer have been published during our review period. Still, only alcohol intake, being overweight and weight gain have shown consistent and strong positive associations with breast cancer risk.

Topics: Alcohol Drinking; Breast Neoplasms; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Energy Intake; Europe; Female; Humans; Micronutrients; North America; Phytoestrogens; Postmenopause; Risk Factors

More than 10 years have passed since the discovery of the second estrogen receptor, estrogen receptor beta (ERbeta). It is now evident that ERalpha is not the only ER in breast cancer cells; in fact, ERbeta is expressed in the majority of breast cancers although at lower levels than in the normal breast. In addition, ERbeta is expressed in breast cancer infiltrating lymphocytes, fibroblasts and endothelial cells, all known to influence tumor growth. By overexpressing or knocking-out ERbeta in breast cancer cell lines, several researchers have investigated its function with respect to proliferation and tumor growth. It appears that ERbeta is anti-proliferative, in many ways antagonising the function of ERalpha. Furthermore, phytoestrogens have a binding-preference for ERbeta and several epidemiological studies indicate a breast cancer preventing effect of this class of compounds. Tamoxifen is one of the standard, adjuvant treatments for ERalpha positive breast cancer, classically thought to mediate its effect through ERalpha. However, in several recent studies, ERbeta has been described as a potential marker for tamoxifen response. In summary, experimental, epidemiological as well as diagnostic studies point towards ERbeta as an important factor in breast cancer, opening up the possibility for novel ERbeta-selective therapies in the treatment of breast cancer.

Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; Estrogen Receptor beta; Humans; Neovascularization, Pathologic; Phytoestrogens

Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown.. Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials.. We identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P=.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P=.003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups.. Based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies.

Topics: Breast Neoplasms; Dietary Supplements; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Endometrial Hyperplasia; Endometrial Neoplasms; Estrogen Replacement Therapy; Female; Follow-Up Studies; Gastrointestinal Diseases; Humans; Incidence; Phytoestrogens; Plant Extracts; Postmenopause; Randomized Controlled Trials as Topic; Risk Assessment; Uterine Hemorrhage

Oestrogen is an important determinant of breast cancer risk. Oestrogen-mimicking plant compounds called phytoestrogens can bind to oestrogen receptors and exert weak oestrogenic effects. Despite this activity, epidemiological studies suggest that the incidence of breast cancer is lower in countries where the intake of phytoestrogens is high, implying that these compounds may reduce breast cancer risk, and possibly have an impact on survival. Isoflavones and lignans are the most common phytoestrogens in the diet. In this article, we present findings from human observational and intervention studies related to both isoflavone and lignan exposure and breast cancer risk and survival. In addition, the clinical implications of these findings are examined in the light of a growing dietary supplement market. An increasing number of breast cancer patients seek to take supplements together with their standard treatment in the hope that these will either prevent recurrence or treat their menopausal symptoms. Observational studies suggest a protective effect of isoflavones on breast cancer risk and the case may be similar for increasing lignan consumption although evidence so far is inconsistent. In contrast, short-term intervention studies suggest a possible stimulatory effect on breast tissue raising concerns of possible adverse effects in breast cancer patients. However, owing to the dearth of human studies investigating effects on breast cancer recurrence and survival the role of phytoestrogens remains unclear. So far, not enough clear evidence exists on which to base guidelines for clinical use, although raising patient awareness of the uncertain effect of phytoestrogens is recommended.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Dietary Supplements; Female; Humans; Isoflavones; Lignans; Neoplasm Recurrence, Local; Phytoestrogens; Risk Factors; Soy Foods

Genistein is an isoflavone with oestrogenic activity that is present in a variety of soy products as a constituent of complex mixtures of bioactive compounds, whose matrix profiles play an important role in determining the overall oestrogenic bioactivity of genistein. We review data on how the profile of soy bioactive compounds can modulate genistein-stimulated oestrogen-dependent tumour growth. Our research has focused on the effects of dietary genistein on the growth of oestrogen (E)-dependent mammary tumours both in vitro and in vivo. Genistein enhances the proliferation of E-dependent human breast cancer tumour growth. In a similar manner, dietary genistein stimulates tumour growth in the chemically-induced (NMU) mammary cancer rodent model. Genistin, the glycoside of genistein, simulates growth similar to that of genistein and withdrawal of either genistein or genistin results in tumour regression. The extent of soy processing modulates the effects of dietary genistein in vivo as soy protein isolate, a highly purified and widely used source of protein that is processed to contain low, medium, and high amounts of isoflavones, stimulate the growth of the E-dependent mammary tumours in a dose dependent manner. In contrast to the more purified diets, studies with soy flour of equivalent genistein levels did not stimulate the growth of E-dependent breast cancer tumours in vivo. However, the size of these tumours also did not regress as is observed in control groups in which oestrogen and genistein have been withdrawn. The expression of the oestrogen-target genes of pS2, progesterone receptor, and cyclin D1 correlates with the growth of E-dependent tumours and has been consistently observed to be induced in response to treatment with dietary genistein. To evaluate whether dietary genistein interacts with current anti-oestrogen breast cancer therapies such as tamoxifen (TAM), we implanted E-dependent tumours into ovariectomized athymic mice and administered oestradiol, oestradiol plus TAM, or oestradiol, TAM, and dietary genistein. In these studies dietary genistein was able to negate the inhibitory effect of TAM on E-stimulated tumour growth. In summary, genistein can act as an oestrogen agonist resulting in proliferation of E-dependent human breast cancer tumours in vivo and its activity can be modulated by the presence of other bioactive components in complex soy foods. Additionally, dietary genistein can negate the inhibitory effects of TAM on E-stimula

Topics: Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Estrogen Replacement Therapy; Female; Genistein; Humans; Phytoestrogens; Plant Extracts; Tamoxifen

Scientific achievements in the last two decades have revolutionized the treatment and prevention of breast cancer. This is mainly because of targeted therapies and a better understanding of the relationship between estrogen, its receptor, and breast cancer. One of these discoveries is the use of synthetic selective estrogen modulators (SERMs) such as tamoxifen in the treatment strategy for estrogen receptor (ER)-positive breast cancer. Hundreds of thousands of lives have been saved because of this advance. Not only is tamoxifen used in the treatment strategy for patients who have breast cancer, but also for prevention in high-risk premenopausal women. Another synthetic SERM, raloxifene, which was initially used to prevent osteoporosis, is also as effective as tamoxifen for prevention in high-risk postmenopausal women. In certain regions of the world, particularly in Asia, a low incidence of breast cancer has been observed. These women have diets that are high in soy and low in fat, unlike the Western diet. Interest in the protective effects of soy derivatives has led to the research of phytoestrogens and metabolites of soy that are described by some as natural SERMs. As a result, many clinical questions have been raised as to whether phytoestrogens, which are also found in other natural foods, can protect against breast cancer. This article reviews the development and role of the more common SERMs, tamoxifen and raloxifene. In addition, this paper will also highlight the emerging studies on phytoestrogens and their similarity and dissimilarity to SERMs.

Topics: Breast Neoplasms; Female; Humans; Molecular Structure; Phytoestrogens; Selective Estrogen Receptor Modulators

Phytoestrogens are used as 'natural' alternatives to HRT and, although epidemiological evidence implies that diets rich in phytoestrogens reduce the incidence of breast cancer, their weak oestrogenicity is also known to stimulate growth in experimental models of breast cancer. This review addresses the question as to how phytoestrogens may protect against breast cancer through their ability to bind preferentially to oestrogen receptor beta, inhibit enzymes that convert circulating steroid precursors into oestradiol and inhibit cell signalling pathways of growth factors.

Topics: Animals; Aromatase Inhibitors; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Estrogens; Humans; Neoplasms, Hormone-Dependent; Phytoestrogens; Receptors, Estrogen; Receptors, Growth Factor; Signal Transduction; Tumor Cells, Cultured

Carcinogenesis of hormone-related cancers involves hormone-stimulated cell proliferation, which increases the number of cell divisions and the opportunity for random genetic errors. In target tissues, steroid hormones are interconverted between their potent, high affinity forms for their respective receptors and their inactive, low affinity forms. One group of enzymes responsible for these interconversions are the hydroxysteroid dehydrogenases, which regulate ligand access to steroid receptors and thus act at a pre-receptor level. As part of this group, the 17beta-hydroxysteroid dehydrogenases catalyze either oxidation of hydroxyl groups or reduction of keto groups at steroid position C17. The thoroughly characterized 17beta-hydroxysteroid dehydrogenase type 1 activates the less active estrone to estradiol, a potent ligand for estrogen receptors. This isoform is expressed in gonads, where it affects circulating levels of estradiol, and in peripheral tissue, where it regulates ligand occupancy of estrogen receptors. Inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 are thus highly interesting potential therapeutic agents for the control of estrogen-dependent diseases such as endometriosis, as well as breast and ovarian cancers. Here, we present the review on the recent development of inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 published and patented since the previous review of 17beta-hydroxysteroid dehydrogenase inhibitors of Poirier (Curr. Med. Chem., 2003, 10, 453). These inhibitors are divided into two separate groups according to their chemical structures: steroidal and non-steroidal 17beta-hydroxysteroid dehydrogenase type 1 inhibitors. Their estrogenic/ proliferative activities and selectivities over other 17beta-hydroxysteroid dehydrogenases that are involved in local regulation of estrogen action (types 2, 7 and 12) are also presented.

Topics: 17-Hydroxysteroid Dehydrogenases; Breast Neoplasms; Enzyme Inhibitors; Estradiol; Estrogens; Estrone; Female; Gossypol; Humans; Neoplasms, Hormone-Dependent; Phytoestrogens

Breast cancer remains the second leading cause of malignancy-related death in women in the USA, regardless of advances in novel therapeutic agents. High priority should be given to research aimed at the study of pharmacological and natural compounds that could potentially prevent the development of breast cancer in susceptible patients. Tamoxifen has been shown to reduce the incidence of estrogen receptor-positive invasive breast cancer in women with a high risk of developing this condition by nearly 50%, and studies in osteoporosis have revealed a similar protective effect of raloxifene in postmenopausal women. The aromatase inhibitors are superior to tamoxifen in reducing the recurrence of breast cancer in postmenopausal women; large clinical trials are currently evaluating the chemopreventive effect of these agents. The list of agents with the potential for chemoprevention in breast cancer is extensive and continues to expand. There is an immense need to develop drugs that will decrease the incidence of estrogen receptor-negative breast cancer in women at high risk of developing the disease. Herein, we review the most important chemopreventive agents in breast cancer and clinical trials that have evaluated their efficacy.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Carotenoids; Chemoprevention; Female; Gonadotropin-Releasing Hormone; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Phytoestrogens; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen

Review of the existing literature suggests that consumption of soy foods or an exposure to a soy isoflavone genistein during childhood and adolescence in women, and before puberty onset in animals, reduces later mammary cancer risk. In animal studies, an exposure that is limited to the fetal period or adult life does not appear to have the same protective effect. A meta-analysis of human studies indicates a modest reduction in pre- and postmenopausal risk when dietary intakes are assessed during adult life. These findings concur with emerging evidence indicating that timing may be vitally important in determining the effects of various dietary exposures on the susceptibility to develop breast cancer. In this review, we address the mechanisms that might mediate the effects of an early life exposure to genistein on the mammary gland. The focus is on changes in gene expression, such as those involving BRCA1 and PTEN. It will be debated whether mammary stem cells are the targets of genistein-induced alterations and also whether the alterations are epigenetic. We propose that the effects on mammary gland morphology and signalling pathways induced by pubertal exposure to genistein mimic those induced by the oestrogenic environment of early first pregnancy.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; BRCA1 Protein; Breast Neoplasms; Cell Proliferation; Disease Susceptibility; Epigenesis, Genetic; Female; Gene Expression; Genes, Tumor Suppressor; Genistein; Humans; Mutation; Phytoestrogens; PTEN Phosphohydrolase; Puberty; Risk Assessment; Sexual Maturation; Soy Foods; Time Factors; Up-Regulation

Phytoestrogens display an array of pharmacologic properties, and in recent years investigation of their potential as anticancer agents has increased dramatically. In this article we review the published literature related to phytoestrogens and breast cancer as well as suggest the possible mechanisms that may underlie the relationship between phytoestrogens and breast cancer.. Electronic searches on phytoestrogens and breast cancer were performed on MEDLINE and EMBASE in June 2007. No date restriction was placed on the electronic search.. We focused on experimental data from published studies that examined the characteristics of phytoestrogens using in vivo or in vitro models. We also include human intervention studies in this review.. We evaluated evidence regarding the possible mechanisms of phytoestrogen action. Discussions of these mechanisms were organized into those activities related to the estrogen receptor, cell growth and proliferation, tumor development, signaling pathways, and estrogen-metabolizing enzymes.. We suggest that despite numerous investigations, the mechanisms of phytoestrogen action in breast cancer have yet to be elucidated. It remains uncertain whether these plant compounds are chemoprotective or whether they may produce adverse outcomes related to breast carcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Aromatase; Breast Neoplasms; Cell Enlargement; Cell Proliferation; Cytochrome P-450 Enzyme System; Diet; Estrogens; Humans; Phytoestrogens; Receptors, Estrogen; Risk Factors; Signal Transduction

To review clinical studies assessing the effect of phytoestrogen supplementation on the signs and symptoms of the climacteric syndrome and on the incidence of breast cancer, cardiovascular disease, and skeletal fractures.. Literature research using PubMed and the Cochrane controlled trials register.. None.. Six systematic reviews and meta-analyses of 25 randomized, controlled trials (RCTs) assessing the use of phytoestrogens for the treatment of the climacteric syndrome were identified. Systematic reviews of RCTs show contradictory results, and meta-analyses demonstrate no statistically significant reduction of vasomotor symptoms for phytoestrogens. Individual RCTs report significant reductions in vasomotor symptoms for red clover and soy phytoestrogens. In selected patient populations, such as in women with early natural postmenopause and mild to moderate vasomotor symptoms, a systematic review of five RCTs found a significant reduction of hot flashes in five out of five RCTs. Twenty-two case-control and cohort studies examined the incidence of breast cancer among women with and without a diet high in phytoestrogens. A meta-analysis of 21 studies found a significantly reduced incidence of breast cancer among past phytoestrogen users. RCTs document beneficial effects of phytoestrogens on surrogate parameters such as bone mineral density, vasodilation, platelet aggregation, insulin resistance, and serum concentrations of triglycerides, high-density lipoprotein, and low-density lipoprotein. None of the available RCTs documents a protective effect of phytoestrogens for the clinical end points of breast cancer, bone fracture, or cardiovascular events.. Based on the available evidence, phytoestrogens should only be used in selected women, i.e., those presenting with mild to moderate vasomotor symptoms in early natural postmenopause. None of the compounds investigated so far have been proven to protect against breast cancer, bone fracture, or cardiovascular disease.

Topics: Breast Neoplasms; Cohort Studies; Estrogens; Female; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Plant Extracts; Randomized Controlled Trials as Topic

Modern consumer needs have stimulated a vast expansion in the dietary supplement market, in an attempt to improve general well being and prevent, rather than cure, disease. Isoflavones form a large part of this market. Their oestrogenic properties are still largely unknown and must be thoroughly researched to ensure they cause no adverse effects, particularly on hormone-dependent reproductive physiology.. As a result of the increasing availability of phytoestrogens, research into their actions now covers a very wide field, many of which impact on reproductive potential. Time of exposure is crucial, as is interaction with other dietary components. Their putative role as chemoprotective agents has been expanded in recent years which may have an indirect impact on fertility by decreasing mortality rates in both men and women.. Phytoestrogens are still a current research topic in reproduction and fertility. Genistein is a putative therapeutic tool in cancer treatment although this must be considered along with evidence that it may cause DNA damage in sperm, depending on the concentration. The effects of phytoestrogen in the body are not limited to oestrogenic action. Much more epidemiological data are required to interpret current molecular studies, and those of previous years.

Topics: Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fertility; Genistein; Humans; Male; Phytoestrogens; Pregnancy; Prostatic Neoplasms; Reproduction; Spermatozoa

Breast cancer continues to be a major challenge for public health, since it is the most common cancer of women in the Western world, and its prevalence is still increasing. In order to achieve better results in the prevention and treatment of breast cancer it is crucial to identify the mechanisms behind its initiation, i.e. the changes and deviations that have occurred in the mammary gland growth. It has long been known that a woman's reproductive history is the strongest breast cancer risk factor if genetic background and age are excluded. The reproductive hormones, and the timing of events leading to changes in these hormones, and consequently, in the mammary gland, are the most important players. However, it has become obvious that dietary components may also contribute to breast cancer risk through their effects on the mammary gland. The past few years have added important information to our knowledge of the mechanisms behind breast cancer initiation at the level of target cells (mammary stem cells) and gene expression (genetic 'fingerprint' associated with persistent pregnancy-induced protection against breast cancer), as well as of the effects of certain dietary factors (steroid action modulators). These results and their links to breast cancer initiation and progression will be discussed.

Topics: Animals; Breast Neoplasms; Diet; Embryonal Carcinoma Stem Cells; Female; Gonadal Steroid Hormones; Humans; Isoflavones; Lignans; Mammary Glands, Human; Models, Biological; Neoplastic Stem Cells; Phytoestrogens; Postmenopause; Pregnancy; Puberty; Risk Factors; Stem Cells

Consumption of phytoestrogen (PE)-rich foods (i. e., soy and flaxseed (FS)) is increasing because of their suggested health benefits. However, recent studies raise concern over the safety of soy and its isoflavones, particularly genistein (GEN), for postmenopausal breast cancer (BC), due to their potential stimulatory effects on human breast tissue and on the growth of existing tumors in rodents. FS, rich in PE lignans, which is metabolized to the mammalian lignans enterolactone (ENL) and enterodiol (END), has consistently been shown to have tumor inhibitory effects in a human clinical trial as well as rodent BC models. Using the preclinical athymic mouse postmenopausal BC model, combining FS with soy protein or GEN with END and ENL, was found to negate the tumor stimulatory effects of soy protein or GEN alone. The mechanism may be related to the modulation of estrogen receptor and MAPK signaling pathways. If these studies can be confirmed in clinical trials, then consumption of combined soy and FS, or their PEs, may reduce the tumor growth stimulatory effect of soy or GEN. This may indicate that if soy is consumed with lignan-rich foods, it may continue to induce its other beneficial health effects, without inducing adverse effect on postmenopausal BC.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Division; Diet; Female; Flax; Genistein; Glycine max; Humans; Isoflavones; Lignans; Phytoestrogens; Postmenopause; Randomized Controlled Trials as Topic; Soybean Proteins

A consensus view of soyabean phyto-oestrogens in clinical interventions in post-menopausal women is presented that is based on data from the EU-funded project Phytohealth. The phyto-oestrogens, primarily genistein and daidzein, were given as soyabean-protein isolates, whole-soyabean foods or extracts, supplements or pure compounds. A comprehensive literature search was conducted with well-defined inclusion or exclusion criteria. For areas for which substantial research exists only placebo-controlled double-blind randomised controlled trials (RCT) conducted on healthy post-menopausal women were included. For emerging areas all available human studies in post-menopausal women were reviewed. In order to make cross comparisons between studies the doses of isoflavones were calculated as aglycone equivalents. There is a suggestion, but no conclusive evidence, that isoflavones from the sources studied so far have a beneficial effect on bone health. The consumption of whole-soyabean foods and soyabean-protein isolates has some beneficial effects on lipid markers of cardiovascular risk. The consumption of isolated isoflavones does not affect blood lipid levels or blood pressure, although it may improve endothelial function. For menopausal symptoms there is currently limited evidence that soyabean-protein isolates, soyabean foods or red-clover (Trifolium pratense L.) extract are effective but soyabean isoflavone extracts may be effective in reducing hot flushes. There are too few RCT studies to reach conclusions on the effects of isoflavones on breast cancer, colon cancer, diabetes or cognitive function. The health benefits of soyabean phyto-oestrogens in healthy post-menopausal women are subtle and even some well-designed studies do not show protective effects. Future studies should focus on high-risk post-menopausal women, especially in the areas of diabetes, CVD, breast cancer and bone health.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cardiovascular Diseases; Female; Genistein; Glycine max; Humans; Isoflavones; Neoplasms; Osteoporosis, Postmenopausal; Phytoestrogens; Postmenopause; Randomized Controlled Trials as Topic

The established role of oestrogen in the development and progression of breast cancer raises questions concerning a potential contribution from the many chemicals in the environment which can enter the human breast and which have oestrogenic activity. A range of organochlorine pesticides and polychlorinated biphenyls possess oestrogen-mimicking properties and have been measured in human breast adipose tissue and in human milk. These enter the breast from varied environmental contamination of food, water and air, and due to their lipophilic properties can accumulate in breast fat. However, it is emerging that the breast is also exposed to a range of oestrogenic chemicals applied as cosmetics to the underarm and breast area. These cosmetics are left on the skin in the appropriate area, allowing a more direct dermal absorption route for breast exposure to oestrogenic chemicals and allowing absorbed chemicals to escape systemic metabolism. This review considers evidence in support of a functional role for the combined interactions of cosmetic chemicals with environmental oestrogens, pharmacological oestrogens, phyto-oestrogens and physiological oestrogens in the rising incidence of breast cancer.

Topics: Aluminum Compounds; Animals; Aromatase Inhibitors; Breast Neoplasms; Cosmetics; Environmental Pollutants; Estrogens; Estrogens, Non-Steroidal; Female; Fibrocystic Breast Disease; Genetic Predisposition to Disease; Humans; Parabens; Phthalic Acids; Phytoestrogens; Radiation-Protective Agents; Siloxanes; Skin Absorption; Triclosan; Ultraviolet Rays

Interest in the physiologic and pharmacologic role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the classes of compounds known as the phytoestrogens, which embody several groups of non-steroidal estrogens, including isoflavones and lignans that are widely distributed within nature. The impact of dietary phytoestrogens on normal biologic processes was first recognized in sheep. Observations of sheep grazing on fields rich in clover and cheetahs fed high soy diets in zoos suggested that flavonoids and related phytochemicals can affect mammalian health. Endogenous estrogens have an important role not only in the hypothalamic-pituitary-gonadal axis, but also in various non-gonadal systems, such as cardiovascular systems, bone, and central nervous systems, and lipid metabolism. There have been several clinical studies of hormone replacement therapy (HRT) in post-menopausal women to examine whether HRT has beneficial effects on the cardiovascular system, bone fractures, lipid metabolism, and Alzheimer's disease. In addition, estrogen contributes to the development of some estrogen-dependent cancers, such as breast cancer and prostate cancer and the number of patients with these cancers is increasing in developed countries. Although recent mega-studies showed negative results for classical HRT in the prevention of some of these diseases, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers. This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens.

Topics: Alzheimer Disease; Animals; Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Female; Glucose Metabolism Disorders; Hormone Replacement Therapy; Humans; Isoflavones; Osteoporosis; Phytoestrogens; Postmenopause; Receptors, Estrogen; Sheep

Lifetime exposure to endogenous steroidal estrogens is an established risk factor for breast cancer, and exposures to other estrogenic and antiestrogenic compounds might also modify the risk of breast cancer. It has been hypothesized that synthetic estrogenic industrial pollutants such as organochlorine compounds and plant-derived estrogenic compounds also modify breast cancer risks; however, recent studies show that levels of organochlorine pollutants are similar in breast cancer patients and controls. There is evidence that synthetic and plant-derived estrogens are selective estrogen receptor modulators, which implies that these compounds can induce tissue-specific, time- and dose-dependent estrogenic or antiestrogenic responses. Therefore, the effects of synthetic or plant-derived estrogens on the incidence of breast cancer depend on both the levels and the timing of exposure to these compounds, particularly during stages of mammary gland development that are extremely sensitive to hormone levels.

Topics: Breast Neoplasms; Environmental Pollutants; Female; Humans; Molecular Structure; Phytoestrogens; Selective Estrogen Receptor Modulators; Time Factors

The impact of soyfood intake on breast cancer risk has been investigated extensively. Much of this focus can be attributed to the soybean being a dietary source that is uniquely rich in isoflavones. The chemical structure of isoflavones is similar to that of estrogen, and isoflavones bind to both estrogen receptors (ER alpha and ER beta) (although they preferentially bind to and activate ER beta) and exert estrogen-like effects under some experimental conditions. Isoflavones also possess nonhormonal properties that are associated with the inhibition of cancer cell growth. Thus, there are several possible mechanisms by which soy may reduce the risk of breast cancer. However, the role of isoflavones in breast cancer has become controversial because, in contrast to the possible beneficial effects, some data from in vitro and animal studies suggest that isoflavones, especially genistein, the aglycone of the main soybean isoflavone genistin, may stimulate the growth of estrogen-sensitive tumors. Limited human data directly address the tumor-promoting effects of isoflavones and soy. Because the use of soyfoods and isoflavone supplements is increasing, it is important from a public health perspective to understand the impact of these products on breast cancer risk in women at high risk of the disease and on the survival of breast cancer patients. To this end, a workshop was held in November 2005 to review the existing literature and to make research recommendations. This paper summarizes the workshop findings and recommendations. The primary research recommendation is that the impact of isoflavones on breast tissue needs to be evaluated at the cellular level in women at high risk for breast cancer.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Carcinogens; China; Clinical Trials as Topic; Congresses as Topic; Disease Models, Animal; Female; Genistein; Humans; Isoflavones; Los Angeles; Neoplasms, Hormone-Dependent; Phytoestrogens; Population Surveillance; Receptors, Estrogen; Risk Factors; Soy Foods

Phytoestrogen is the bioactive substance from plant, with structure is very simliar to that of estrogen. Phytoestrogen is mainly comprises of isoflavone, lignan and coumarin. Epidemiological restrarch shows that the increasing the uptake phytoestrogen of can reduce the morbidities of breast and other cancers. In this paper, the food source, characteristic and relevant researches both in vitro and in vivo were reviewed, and its mechanisms of intervening breast cancer were also discussed.

Topics: Animals; Antioxidants; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Coumarins; DNA Topoisomerases, Type II; Female; Humans; Isoflavones; Lignans; Phytoestrogens; Plants, Medicinal; Protein-Tyrosine Kinases

Review on complementary and alternative therapies for climacteric symptoms.. Search for publications about complementary or alternative treatments for climacteric symptoms based on Cochrane Library and Medline (1966-2006) including the references from the identified clinical trials and reviews.. Cimicifuga may influence climacteric symptoms, especially hot flushes. Results for phytoestrogens, hop and Salvia seem promising but are less convincing. St. John's wort is an option for the treatment of moderate depressive symptoms. Phytoestrogens seem to have some potential for the prevention of osteoporosis and cardiovascular diseases. Results for the influence of lifestyle on hot flushes are conflicting, but interventions have demonstrated their use for the prevention of osteoporosis and cardiovascular diseases.. Lifestyle modifications, Cimicifuga and phytoestrogens may relieve climacteric symptoms. Phytoestrogens and Cimicifuga should not be given to breast cancer survivors.

Topics: Acupuncture; Adult; Aged; Aromatherapy; Breast Neoplasms; Cardiovascular Diseases; Case-Control Studies; Cimicifuga; Climacteric; Cohort Studies; Complementary Therapies; Contraindications; Depression; Diet; Dioscorea; Exercise; Female; Homeopathy; Hot Flashes; Humans; Humulus; Hydrotherapy; Hypericum; Life Style; Longitudinal Studies; MEDLINE; Middle Aged; Osteoporosis; Phytoestrogens; Phytotherapy; Plant Extracts; Postmenopause; Prospective Studies; Randomized Controlled Trials as Topic; Relaxation Therapy; Salvia; Stress, Physiological; Surveys and Questionnaires; Survivors; Trifolium

With the increasing numbers of breast cancers survivors, menopause, its symptoms, and its physical complications are becoming more prevalent problems in this patient population. Hormonal replacement, which has been the cornerstone therapy of menopausal related symptoms for decades, recently has been shown to increase breast cancer incidence as well as risk of recurrence and no longer should be recommended. Menopausal symptoms and complications such as hot flashes, vaginal dryness, dyspareunia, and osteoporosis leading to fractures have a negative impact on the quality of life of both breast cancer survivors and the general postmenopausal population. The purpose of this review is to discuss the evidence for the use of alternative therapies for menopausal symptoms, thus providing guidance and recommendations that should facilitate therapeutic decisions in the daily practice of medical oncologists and primary care physicians.

Topics: Breast Neoplasms; Cardiovascular Diseases; Complementary Therapies; Estrogens; Female; Genitalia, Female; Hot Flashes; Humans; Menopause; Menopause, Premature; Osteoporosis; Phytoestrogens; Quality of Life; Survivors; Vasomotor System

The majority of breast cancers are oestrogen dependent and in postmenopausal women the supply of oestrogens in breast tissue is derived from the peripheral conversion of circulating androgens. There is, however, a paradox concerning the epidemiology of breast cancer and the dietary intake of phytoestrogens that bind weakly to oestrogen receptors and initiate oestrogen-dependent transcription. In Eastern countries, such as Japan, the incidence of breast cancer is approximately one-third that of Western countries whilst their high dietary intake of phytoestrogens, mainly in the form of soy products, can produce circulating levels of phytoestrogens that are known experimentally to have oestrogenic effects. Indeed, their weak oestrogenicity has been used to advantage by herbalist medicine to promote soy products as a natural alternative to conventional hormone replacement therapy (HRT). Such usage could increase in light of recent evidence that long-term HRT usage may be associated with an increased risk of breast cancer with a consequent reduction in prescription rates. So, are phytoestrogens safe as a natural alternative to HRT and could they be promoters or protectors of breast cancer? If they are promoters, then we must assume that it is due to their oestrogenic effect. If they are protectors, then other actions of phytoestrogens, including their ability to inhibit enzymes that are responsible for converting androgens and weak oestrogens into oestradiol, must be considered. This paper addresses these questions by reviewing the actions of phytoestrogens on oestrogen receptors and key enzymes that convert androgens to oestrogens in relation to the growth of breast cancer cells. In addition, it compares the experimental and epidemiological evidence pertinent to the potential beneficial or harmful effects of phytoestrogens in relation to the incidence/progression of breast cancer and their efficacy as natural alternatives to conventional HRT.

Topics: Animals; Breast Neoplasms; Carcinogens; Female; Humans; Phytoestrogens; Receptors, Estrogen

Lignan is an important phytoestrogen with weakly estrogenic and anti-estrogenic properties, and possesses diverse bioactivities, including antioxidation, antitumor and antivirus etc. In particular, it may prevent hormone-dependent diseases, such as breast cancer, prostate cancer and benign prostatic hyperplasia. However, many important scientific problems have not been constrained, whether do the metabolites of lignans from foods have their potential genic toxicity? What are the anticancer mechanisms of lignans? What is the dosage of lignans to achieve the desired biological effect? In this paper, the references on lignans have systematically been reviewed in the following aspects: classification, distribution, metabolism, pharmacological activities and analytical methods, and a prospective of future studies on lignans is also elucidated.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Female; Humans; Lignans; Male; Phytoestrogens; Plants, Medicinal; Prostatic Neoplasms

Phytoestrogens are naturally occurring plant-derived phytochemicals, whose common biological roles are to protect plants from stress or to act as part of a plant's defense mechanism. Although composed of a wide group of nonsteroidal compounds of diverse structure, phytoestrogens have been shown to bind estrogen receptors and to behave as weak agonist/antagonist in both animals and humans. Phytoestrogens include mainly isoflavones (IF), coumestans, and lignans. These compounds are known to be present in fruits, vegetables, and whole grains commonly consumed by humans. IF are found in legumes--mainly soybeans--whereas flaxseed is a major source of lignans, and coumestans are significantly present in clover, alfalfa and soybean sprouts. 8-Prenyl flavonoids are common in vegetables. Bioavailability of IF requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the following uptake by enterocytes and the flow through the peripheral circulation. Following absorption, IF are then reconjugated mainly to glucuronic acid and to a lesser degree to sulphuric acid. Gut metabolism seems key to the determination of the potency of action. Several epidemiological studies correlated high dose consumptions of soy IF with multiple beneficial effects on breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis and stroke, and neurodegeneration. For the relief of menopausal symptoms a consumption of 60 mg aglycones/day has been suggested; for cancer prevention a consumption between 50 and 110 mg aglycones/day is considered beneficial to reduce risks of breast, colon and prostate cancer; to decrease cardiovascular risk a minimum intake of 40-60 mg aglycones/day, together with about 25 g of soy protein has been suggested. For improvement in bone mineral density, 60-100 mg aglycones/day for a period of at least 6-12 months could be beneficial.

Topics: Biological Availability; Breast Neoplasms; Coronary Disease; Diet; Fruit; Glycine max; Health Promotion; Humans; Intestinal Absorption; Isoflavones; Osteoporosis; Phytoestrogens; Safety; Vegetables

Despite years of intensive research, breast cancer remains a major cause of death among women. New strategies to combat breast cancer are being developed, one of the most exciting of which is the use of chemopreventive agents. Resveratrol (RES) is a polyphenolic compound found in plants that seems to have a wide spectrum of biological activity. RES has been shown to afford protection against several types of cancer. This review summarizes the chemopreventive effects of RES at the three major stages of breast carcinogenesis: initiation, promotion, and progression. It has anti-oxidant and anti-inflammatory properties, and may induce apoptosis as well as modulate cell cycle and estrogen receptor function in breast cancer cell lines. Although RES has shown remarkable promise as a potent chemopreventive agent in breast cancer, further studies are needed to etablish its usefulness.

Topics: Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Division; Humans; Phosphatidylinositol 3-Kinases; Phytoestrogens; Resveratrol; Signal Transduction; Stilbenes; Xenobiotics

Between one-third to one-half of all breast cancers are steroid sensitive. Steroid-pathway enzymes (sulfatase, 17beta-hydroxysteroid dehydrogenases, aromatase and sulfotransferases) are thus prime candidates for therapeutic approaches based on the control of intacrine activity. Some phytoestrogens, ubiquitous in our diet, are inhibitors of these enzymes. Such a therapeutic potential has stimulated research and progress has been achieved during the last years. Complementary to previous reviews on phytoestrogens, this contribution covers the estrogen pathway inhibition effects of these compounds and special attention will be given to isoflavonoids, flavonoids and lignans. Furthermore, the research on structurally-related compounds as therapeutic agents will be discussed briefly.

Topics: Breast Neoplasms; Dietary Supplements; Female; Humans; Phytoestrogens; Phytotherapy; Selective Estrogen Receptor Modulators

The benefits of plant extracts from soy and red clover as alternatives to conventional hormone replacement therapy (HRT) have been debated in the past. Here, an attempt has been made to summarize the biochemical and pharmacological data in the light of clinical aspects. Red clover and soy extracts contain isoflavones, which have a high affinity to estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and androgen receptor (AR). The higher affinity to ERbeta compared to ERalpha has been used as an explanation why red clover extracts function as food additives to treat menopausal disorders and may reduce risk of breast cancer. Biochemical analysis shows that these representatives of phytoestrogens have multiple actions beside selective estrogen receptor modulator (SERM)-activity. They act as selective estrogen enzyme modulators (SEEMs), have antioxidant activity and interact with transcription factors such as NF-kappaB. Furthermore, it is indicated that they have protective effects on osteoporosis and the cardiovascular system. Currently 40-50mg of isoflavones (biochanin A, daidzein, formononetin and genistein) are recommended as daily dose. This recommendation is based on the daily intake of phytoestrogens in a traditional Japanese diet.

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Estrogen Replacement Therapy; Female; Humans; Isoflavones; Models, Animal; Molecular Structure; Osteoporosis; Phytoestrogens; Receptors, Steroid; Selective Estrogen Receptor Modulators; Trifolium; Vitamin A

Phytoestrogens are plant-derived hormone-like diphenolic compounds of dietary origin that are present at high levels in plasma of subjects living in areas with low atherosclerosis and cancer incidence. The term phytoestrogen is commonly applied to the soy isoflavones genistein, daidzein and glycitein. As outlined in a previous review article in this journal by Adlercreutz and Mazur 1, these compounds are weakly estrogenic and appear to influence the cardiovascular system, the production, metabolism and biological activity of sex-hormones, as well as malignant cell proliferation, differentiation and angiogenesis. Recently skepticism has developed concerning the true potential of phytoestrogens to beneficially modify these processes. A critical analysis of the early findings from supplementing the diet with soy protein has failed to confirm phytoestrogens as the responsible agent for beneficial cardiovascular effects, be it by way of lipid reduction, vasodilation or lipoprotein oxidation. Furthermore, contrasting data have been reported on the potential of phytoestrogens to prevent hormone-dependent cancers (e.g. breast and prostate) and to successfully treat post-menopausal complaints, an indication for which they are widely used. These potentially negative findings have led health authorities in several countries to suggest maximum daily intake levels for phytoestrogens. There is now growing interest in the use of soy products containing low levels of phytoestrogens and in research on other phytoestrogen free legumes such as lupin.

Topics: Breast Neoplasms; Cardiovascular System; Female; Humans; Male; Phytoestrogens; Prostatic Neoplasms

Worldwide, each year approximately one million women are newly diagnosed with breast cancer (BC), in Germany 65 new cases per 100,000 inhabitants are registered, yearly. The fact that incidence has been rising in parallel with economic development indicates that environmental factors might play a role in the causation of BC. Migrational data have pointed to nutrition as one of the more relevant external factors involved. Preventive dietary advice often includes a reduction of alcohol, red meat and animal fat and increasing the intake of vegetables, fruit and fibre and lately, phyto-estrogens from various sources. Clearly, the scientific basis for these recommendations appears sparse. The available prospective data from epidemiological studies and interventional trials do not support the overall hypothesis that higher fat-intakes are a relevant risk factor for BC development, more important seems the relative distribution of various fatty acids. A non-vegetarian eating habit (consumption of animal products) per se does not elevate BC risk, while consumption of broiled or deep fried meats cannot be ruled out as a risk factor in genetically susceptible individuals. It appears prudent to abstain from regular and increased alcohol consumption. This should be particularly true for pubescent girls, in whom glandular breast tissue is particularly vulnerable. In general, if alcohol is consumed on a regular basis, a sufficient supply of fresh vegetables and fruit is essential. While there is no overall protective effect of a high fruit and vegetable consumption speculation remains over possible beneficial effects of certain subcategories, especially brassica vegetables like broccoli, cauliflower and cabbage. In essence, regional differences in BC incidence are probably partially attributable to life long dietary habits. There is no need to adopt a foreign dietary plan in order to protect oneself against BC. Traditional western diets also have their beneficial ingredients that should be regular constituents in our meals. Lignans from traditionally made sourdough rye bread, linseed/flaxseed and berries are local sources of potentially canceroprotective phyto-estrogens. Furthermore, indole-3-carbinol rich cabbage species might contribute to BC protection by diet. Nevertheless, clear cut recommendations for or against single nutrients or secondary plant metabolites are not yet possible, lacking sufficient data on individual bioavailability, safety and long term outcome

Topics: Alcohol Drinking; Animals; Breast Neoplasms; Dietary Fats; Dietary Fiber; Female; Fishes; Fruit; Humans; Meat; Nutritional Physiological Phenomena; Phytoestrogens; Risk; Vegetables

The incidence of hormone-dependent cancers, such as those of the breast and prostate, is much lower in Eastern countries such as China and Japan in comparison with the Western world. Diet is believed to have a major effect on disease risk and one group of compounds, the phyto-oestrogens, which are consumed in large amounts in Asian populations, have been implicated in cancer protection. This view follows the finding that plasma and urinary levels of phyto-oestrogens are much higher in areas where cancer incidence is low in comparison with areas of high cancer incidence. The phyto-oestrogens are comprised of two main groups; the isoflavones and lignans. Of the isoflavones, genistein and daidzein have been the most widely studied. These compounds have been shown to possess anticancer properties; however their precise mechanism of action remains to be elucidated. In comparison, few studies have investigated the effects of lignans in breast and prostate cancer. In vitro studies have shown that genistein exerts biphasic effects on cancer cell growth, stimulating growth at low concentrations (<10 microm) and inhibiting growth at high concentrations (>10 microm), which suggests that low phyto-oestrogen levels may stimulate cancer growth in vivo. Plasma phyto-oestrogen concentrations of >10 microm cannot be achieved by dietary intake and therefore the timing of exposure to phyto-oestrogens may be of the utmost importance in determining their chemopreventive effects. The present paper reviews the effects of phyto-oestrogens on breast and prostate cancer in vivo and in vitro and discusses possible mechanisms of action via which these compounds may exert their effects.

Topics: Animals; Breast Neoplasms; Cell Division; Diet; Female; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms; Tumor Cells, Cultured

Phytoestrogens are polyphenol compounds of plant origin that exhibit a structural similarity to the mammalian steroid hormone 17beta-oestradiol. In Asian nations the staple consumption of phyto-oestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic stimulation of oestrogen receptor-positive breast cancer cell lines and the antagonism of tamoxifen activity at physiological phyto-oestrogen concentrations. Conversely, phyto-oestrogen ingestion by rodents is associated with the development of less aggressive breast tumours with reduced metastatic potential. Despite the present ambiguity, current data do suggest a potential benefit from use of phyto-oestrogens in breast cancer chemoprevention and therapy. These aspects are discussed.

Topics: Adolescent; Adult; Age Factors; Aged; Animals; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Asia; Breast Neoplasms; Child; Emigration and Immigration; Enzyme Inhibitors; Estrogens; Feeding Behavior; Female; Humans; Infant; Isoflavones; Mammary Neoplasms, Experimental; Mice; Middle Aged; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Postmenopause; Premenopause; Prevalence; Protein-Tyrosine Kinases; Receptors, Estrogen; Signal Transduction; Structure-Activity Relationship; United States

Some of the important health issues for postmenopausal women include cardiovascular disease, osteoporosis, breast cancer, and relief of menopausal symptoms. Ovariectomized cynomolgus monkeys (Macaca fascicularis) have many strengths as models for research in this area including a close phylogenetic relationship to humans, similarities in lipid/lipoprotein metabolism and coronary artery anatomy, similar skeletal anatomical and morphological characteristics, mammary glands with similar pathophysiological characteristics, and a 28-day menstrual cycle with similar hormonal fluctuations. Monkeys (macaques) also experience declining ovarian function and irregular menstrual cycles (natural menopause) when they approach 24 to 29 yr of age. However, because of their very short life span after natural menopause, ovariectomized macaques are used to model postmenopausal women. The cynomolgus monkey model has been useful in defining the potential cardiovascular benefits of soy foods and soy supplements; however, it remains unclear whether the observations are generalizable to all women or only to those who, like cynomolgus monkeys, convert the soy isoflavone daidzein to the metabolite equol. Particularly important has been the use of the cynomolgus monkey model to understand the effects of soy on breast health. There is evidence from a cynomolgus monkey trial to suggest that soy/soy phytoestrogens have no estrogen agonist effects for breast. Finally, soy/soy phytoestrogens do not appear to be an adequate alternative to postmenopausal hormone therapy. Nevertheless, important attributes of soy have been identified, and it may have potential as a complementary component to hormone therapy.

Topics: Animals; Arteries; Bone and Bones; Breast Neoplasms; Cardiovascular Diseases; Female; Hot Flashes; Humans; Isoflavones; Lipids; Lipoproteins; Macaca fascicularis; Models, Animal; Phytoestrogens; Plant Preparations; Postmenopause; Soy Foods

Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH)(2)-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1 alpha-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-beta (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 micromol/L. The high concentration of 50 micromol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.

Topics: Animals; Breast Neoplasms; Carcinoma; Colorectal Neoplasms; Diet; Female; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Vitamin D

Chemicals known to disrupt the endocrine system of animal models are assessed for their potential impact on the health of menopausal and postmenopausal women. These "endocrine disrupters" consist of two groups of compounds - man-made and naturally occurring. There is some evidence to suggest that the naturally occurring phytoestrogens, derived from plant material, may have some beneficial effects on menopausal symptoms and the risk of breast cancer, cardiovascular disease and osteoporosis. Further studies are required to confirm these possibilities. Some man-made environmental pollutants appear to increase the risk of breast cancer, although again the evidence is inconclusive. Mechanistic experiments indicate that these chemicals interact with oestrogen receptors and alter metabolism in a number of different ways, some of which may be important in postmenopausal women. Further investigation of the differences in mode of action between the man-made and the natural endocrine disrupters may lead to important insights into their effects on women's health.

Topics: Aged; Animals; Breast Neoplasms; Coronary Disease; Endocrine System; Environmental Pollutants; Female; Humans; Menopause; Middle Aged; Neoplasms, Hormone-Dependent; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Risk Assessment; Uterine Neoplasms; Women's Health

The data concerning post-menopausal hormone replacement therapy (HRT) were recently completely modified. The aim of this review is to present the last studies about post-menopausal HRT and to describe new alternatives to this treatment.. In May 2002, the women's health initiative (WHI) trial of post-menopausal HRT was interrupted earlier than expected. The studied hormonal formulation in this arm of the WHI trial was the association of conjugated equine estrogens and medroxyprogesterone. The reason for termination was an increased risk of breast cancer and myocardial infarction in the hormone-therapy group. Later, reports confirmed that this type of HRT could not be used any more for the primary prevention of coronary heart disease even if the absolute risk remained low. There is an increased risk for venous thromboembolism with post-menopausal estroprogestative replacement. This risk does not seem to exist with transdermal estrogens. The other WHI findings concerned the lack of protection against dementia and cognitive decline. On the contrary, osteoporotic hip fractures and colorectal cancers were reduced in the treated group. In April 2004, the estrogen only arm of the same WHI study was also prematurely interrupted because of an increase in the incidence of stroke. The risk of breast cancer was on the contrary not increased after 6.8 years, raising the question of the eventual role of progestins.. The impact of the WHI trial on clinical practice was very important since then. The "Agence Francaise de sécurité sanitaire des produits de santé" (AFSSAPS) edited in May 2004 a public recommendation limiting indication for HRT to patients with severe climacteric symptoms. The treatment must now be prescribed for the shortest time and at the minimal dose. The patient has to be precisely informed about the risks with HRT and the practitioner has to re-evaluate his prescription annually. Hormonal or non-hormonal alternatives have also to be considered as phytoestrogens and tibolone for hot flashes, and raloxifene and diphosphonates for osteoporosis prevention. In any case, a healthy diet, exercise and smoking cessation should be encouraged.

Topics: Breast Neoplasms; Clinical Trials as Topic; Equilin; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Life Style; Medroxyprogesterone; Menopause; Myocardial Infarction; Phytoestrogens; Risk Assessment; Thromboembolism; Treatment Outcome

Perimenopausal period is associated with the reduction of endogenous estrogens which might lead to many disorders of general health in women. Traditional hormone replacement therapy (HRT) is effective for controlling vasomotor symptoms and reducing the risk of cardiovascular disease and osteoporosis in postmenopausal women. However, according to the latest studies, many women are reluctant to initiate this therapy because of concerns regarding the benefits and risks considering contraindications and side effects of it. Therefore, a lot of studies were carried out to find the influence of phytoestrogens on menopausal symptoms. Phytoestrogens are defined as naturally occurring compounds, found in plants; they have a variety of activities: estrogenic and antiestrogenic. Could phytoestrogens be used as an alternative to hormonal therapies for the management of menopausal symptoms?

Topics: Breast Neoplasms; Cardiovascular Diseases; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Isoflavones; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Poland; Women's Health

Phytoestrogens are natural plant substances. The three main classes are isoflavones, coumestans, and lignans. Phytoestrogens have anticarcinogenic potential, but they have also significant estrogenic properties. For an evaluation of the effect of phytoestrogens on breast cancer risk we reviewed the analytical epidemiological data. A total of 18 studies were included. Up to now, there are 13 studies that have assessed the direct relation between the individual dietary intake of soy products and the risk of breast cancer. Overall, results do not show protective effects, with the exception maybe for women who consume phytoestrogens at adolescence or at very high doses. Only four of these 13 studies are prospective, and none of them found statistically significant breast cancer reductions. Four studies assessed urinary isoflavones excretion in relation to breast cancer. Three of these are case control studies, where excretion was measured after breast cancer occurrence and thus seriously limiting causal interpretation of the results. The only prospective study with urinary measurements before breast cancer occurrence was done in a Dutch postmenopausal population and showed a non-significant breast cancer risk reduction for high excretion. Three studies measured enterolactone (lignan): two case control studies reported a preventive effect on breast cancer risk, but the only prospective study did not . In conclusion, few prospective studies (n = 5) were done to assess the effects of phytoestrogens on breast cancer risk. None of them found protective effects. However, these prospective studies did not focus on 'age at consumption', which seems to be important based on results from dietary case control studies done so far.

Topics: 4-Butyrolactone; Adolescent; Adult; Age Factors; Breast Neoplasms; Case-Control Studies; Climacteric; Diet; Estrogens; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Plants; Prospective Studies; Risk

Interest in the physiological role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the class of compounds known as the phytoestrogens, which embody several groups of non-steroidal oestrogens including isoflavones & lignans that are widely distributed within the plant kingdom. Data from animal and in vitro studies provide plausible mechanisms to explain how phytoestrogens may influence hormone dependent states, but although the clinical application of diets rich in these oestrogen mimics is in its infancy, data from preliminary studies suggest potential beneficial effects of importance to health. Phytoestrogens are strikingly similar in chemical structure to the mammalian oestrogen, oestradiol, and bind to oestrogen receptors (ER) with a preference for the more recently described ER beta. This suggests that these compounds may exert tissue specific effects. Numerous other biological effects independent of the ER (e.g. antioxidant capacity, antiproliferative and antiangiogenic effects) have been ascribed to these compounds. Whether phytoestrogens have any biological activity in humans, either hormonal or non hormonal is a contentious issue and there is currently a paucity of data on human exposure. Much of the available data on the absorption and metabolism of dietary phytoestrogens is of a qualitative nature; it is known that dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver, circulated in plasma and excreted in urine. Recent studies have addressed quantitatively what happens to isoflavones following ingestion--with pure compound and stable isotope data to compliment recent pharmacokinetic data for soy foods. The limited studies conducted so far in humans clearly confirm that soya isoflavones can exert hormonal effects. These effects may be of benefit in the prevention of many of the common diseases observed in Western populations (such as breast cancer, prostate cancer, menopausal symptoms, osteoporosis) where the diet is typically devoid of these biologically active naturally occurring compounds. However since biological effects are dependent on many factors including dose, duration of use, protein binding affinity, individual metabolism and intrinsic oestrogenic state, further clinical studies are necessary to determine the potential health effects of these compounds in specific population groups. However we cur

Topics: Animals; Breast Neoplasms; Coronary Disease; Diet; Endometrial Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Infant; Infant Food; Intestinal Absorption; Isoflavones; Lignans; Male; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Premenopause; Risk Factors

The use of phytoestrogens as a natural source of estrogen has been rapidly accepted by consumers for various remedial or preventive purposes, including breast cancer prevention. Phytoestrogens exhibit mixed weak estrogen agonist/antagonist properties and antioxidative activity. They may play a significant inhibitory role during the initiation and promotional phases of cancer development. Experimental and physiologic studies provide much of the evidence on the inverse association between breast cancer risk and phytoestrogen intake. Research in humans has been limited to observational (case-control) epidemiologic studies and is far from conclusive. A critical evaluation through controlled trials of phytoestrogens' breast cancer-protective role needs to be performed before they are adopted as chemopreventive agents.

Topics: Breast Neoplasms; Case-Control Studies; Estrogens, Non-Steroidal; Evidence-Based Medicine; Female; Humans; Isoflavones; Phytoestrogens; Phytotherapy; Plant Preparations

Phytoestrogens are weak estrogens found concentrated in soybeans. Americans consume phytoestrogens primarily in traditional soy foods, soymilk and isolated soy protein added during food processing or consumed as a beverage. Extracted phytoestrogens are also marketed in numerous forms as dietary supplements regulated under the Dietary Supplement Health and Education Act. Consumers of phytoestrogen supplements tend to be peri- and postmenopausal women looking for an alternative to hormone therapy. Although there are no approved health claims for phytoestrogens at this time, numerous claims are being made regarding benefits to heart, bone, breast and general menopausal health. The data supporting these claims are generally not strong. The strongest data show that phytoestrogens reduce the number and intensity of hot flashes, although the reduction is a modest 10-20%. The studies showing cholesterol lowering have used soy protein rather than phytoestrogen extracts. The soy protein appears to be required for this effect, although phytoestrogen extracts may have other beneficial effects on the cardiovascular system. The data on bone metabolism are suggestive of possible benefits whereas the effects on the breast are the most poorly understood. Although most animal studies have shown cancer-preventive effects, a few recent studies suggest that soy phytoestrogens may stimulate breast cancer cell growth under certain circumstances. Before recommendations regarding phytoestrogen supplements can be safely made, we must have more information on the effects of the extracts on bone, heart and breast health. Until safety with respect to breast cancer is established, phytoestrogen supplements should not be recommended, particularly for women at high risk of breast cancer.

Topics: Animals; Bone Diseases; Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations

Phyto-oestrogens are oestrogenic compounds found in plants and consist of isoflavones, lignans and coumestans. Epidemiological studies provide evidence for a protective role of isoflavones, and to a lesser extent lignans, against the development of numerous chronic diseases, including several cancers, cardiovascular disease and osteoporosis. The structural similarity of phyto-oestrogens to endogenous oestrogens has prompted the hypothesis that phyto-oestrogens exert hormonal or anti-hormonal effects relevant to the risk of hormone-dependent disease and/or their suitability as a dietary alternative to hormone replacement therapy. The many human studies that have evaluated the effects of isoflavones and lignans on various endpoints relating to risk of various diseases have greatly increased knowledge of how these compounds behave. At the same time, additional questions have been generated. For example, the increasing interest in extracting isoflavones from the soybean for incorporation into dietary supplements has raised important concerns regarding safety and efficacy. Overall, it is clear that phyto-oestrogens are an area of active and advancing research with great potential to continue to affect human health.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cardiovascular Diseases; Female; Humans; Isoflavones; Male; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms

Phytoestrogens are defined to be plant chemicals that modify estrogenic effects in the body by binding to the estrogen receptors in mammals. Isoflavones, coumestane, lignan, and prenylflavones are examples of these, with isoflavones from soy foods and lignans from rye being a major dietary contribution. Mechanisms of cancer prevention by these phytoestrogens are reviewed, and human epidemiological studies, especially for breast and prostate cancers, are summarized and the results discussed.

Topics: Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk; Soybean Proteins

Phytoestrogens are a group of plant-derived substances that are structurally or functionally similar to estradiol. There has been much interest in the potential role of phytoestrogens in cancer prevention and treatment of estrogen-deficient states. This review summarizes the evidence for phytoestrogen risks and benefits relevant to the breast cancer survivor, including prevention of a second primary breast cancer or metastatic disease, reduction in menopausal symptoms, and interactions with tamoxifen. Epidemiological data suggest a breast cancer protective role for phytoestrogens, and there is some supporting clinical data, but they are far from conclusive. In addition, there is some evidence that genistein, the most prevalent isoflavone in soy, can stimulate estrogen receptor-positive (ER+) breast cancer growth and interfere with the antitumor activity of tamoxifen at low levels. Given current knowledge, women who have ER+ tumors should not increase their phytoestrogen intake. Several studies suggest an inhibitory effect on ER- breast cancer cell growth, and it may be reasonable for women with ER- tumors to safely consume soy and possibly other phytoestrogens. However, the optimal amount and source are not clear. More research is needed to clarify the role of phytoestrogens in breast cancer prevention and in treating estrogen-deficient diseases in women who have had breast cancer.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Female; Humans; Isoflavones; Neoplasm Recurrence, Local; Phytoestrogens; Phytotherapy; Plant Preparations; Receptors, Estrogen; Risk Assessment; Survivors; Tamoxifen

Many women seek alternatives to hormone replacement therapy (HRT). Phytoestrogens are nonsteroidal compounds with estrogenic or antiestrogenic properties. Six of the 16 clinical trials suggest a significant reduction in alleviating symptoms but to a lesser degree than HRT. A meta-analysis showed that phytoestrogens improve lipid profile. The 14 recent clinical trials led, however, to divergent findings. Small clinical trials suggested a protective effect of phytoestrogens on bone metabolism. High concentration of phytoestrogens was associated with a reduction in breast cancer risk in case-control studies.

Topics: Aged; Bone Density; Breast Neoplasms; Cardiovascular Diseases; Case-Control Studies; Clinical Trials as Topic; Female; Hormone Replacement Therapy; Humans; Isoflavones; Lipids; Menopause; Middle Aged; Osteoporosis; Phytoestrogens; Plant Preparations; Risk Factors

The utilization of computer modeling, site-directed mutagenesis, inhibition kinetic analysis and reaction metabolite analysis allows us to better understand the structure-function relationship between aromatase and its inhibitors. Our results have helped in determining how steroidal and nonsteriodal aromatase inhibitors bind to the active site of the enzyme. This information has also aided in the understanding of the reaction mechanism of aromatase. Furthermore, our structure-function studies of aromatase have generated important information for predicting how environmental chemicals interact with the enzyme. During the last 2 years, a new aromatase computer model based on the X-ray structure of rabbit cytochrome P450 2C5 has been generated and used to evaluate the results obtained from new aromatase mutants produced in this laboratory. In addition, we have succeeded in the expression and purification of functionally active aromatase using an Escherichia coli expression method. The catalytic properties of this recombinant aromatase are similar to those properties exhibited by the human placental aromatase preparation and the mammalian cell-expressed enzyme. The E. coli expressed aromatase will be very useful for further structure-function studies of aromatase. Our laboratory has also evaluated the growth-inhibiting activity of aromatase inhibitors in estrogen receptor-positive breast cancer using three-dimensional cell cultures of aromatase-over expressing MCF-7 and T-47D cell lines (i.e. MCF-7aro and T-47Daro). Our results demonstrate that these three-dimensional cultures are valuable approaches to assess the growth-inhibiting activity of aromatase inhibitors. Finally, we have identified several phytochemicals to be potent inhibitors of aromatase. To demonstrate the impact of the phytochemicals on estrogen formation in vivo, we showed that the intake of anti-aromatase chemicals from red wine was capable of suppressing MCF-7aro-mediated tumor formation in nude mice and aromatase-induced hyperplasia in a transgenic mouse model in which aromatase is over-expressed in the mammary tissue.

Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Line, Tumor; Enzyme Inhibitors; Humans; Isoflavones; Models, Molecular; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Recombinant Proteins; Structure-Activity Relationship

Human diet contains a series of bioactive vegetal compounds that can improve human health. Among these, there has been a special interest for phytoestrogens. This article reviews the evidence about the potential benefits of phytoestrogens for human health. Forty eight manuscripts were selected for their study design and relevance to human health. The cell growth inhibitory effects of phytoestrogens and their implication in breast cancer are reviewed. Also the effects of these compounds on serum lipid levels and the effectiveness of a phytoestrogen derivate, ipriflavone, on the prevention of osteoporosis are analyzed. Although these compounds have a great potential for improving health, there is still not enough evidence to recommend the routine use of phytoestrogens.

Topics: Breast Neoplasms; Cardiovascular Diseases; Diet; Female; Glycine max; Humans; Hypolipidemic Agents; Isoflavones; Menopause; Osteoporosis; Phytoestrogens; Plant Preparations

Phytoestrogens are plant constituents that possess either estrogenic or antiestrogenic activity. Although their activities are weak as compared with human endogenous estrogens, the consumption of phytoestrogens may have clinically significant consequences. A number of botanicals, or the compounds contained therein, have been identified as putative estrogenic agents, but consensus in the biomedical community has been hampered by conflicting data from various in vitro and in vivo models of estrogenic activity. Phytoestrogens may serve as chemopreventive agents while at the same time being capable of promoting growth in estrogen receptor positive cancer cell lines. Furthermore, they may exert their estrogenic influence through receptor-dependent and/or receptor-independent mechanisms. These findings have led to speculation that phytoestrogen intake might be ill advised for patients at an increased risk for hormone-dependent cancers, cancer patients, or cancer survivors. This article will attempt to sort out discrepancies between various experimental models and establish whether certain herbs possess estrogenic activity. The review will focus on 5 popular botanical dietary supplements: Trifolium pratense (red clover), Cimicifuga racemosa (black cohosh), Humulus lupulus (hops), Angelica sinensis (dong quai), and Glycyrrhiza glabra (licorice). It will address their mechanisms of action, clinical evidence bases, and implications for use in cancer.

Topics: Animals; Breast Neoplasms; Complementary Therapies; Dietary Supplements; Female; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Phytoestrogens; Phytotherapy; Plant Preparations; Prognosis; Receptors, Estrogen; Risk Assessment; Survival Analysis

The incidence rate of breast cancer varies worldwide, with the rate of Japanese and other Asian women only being a third to a half of that for Caucasian women. Recent research has suggested that consumption of phytoestrogen-rich foods may reduce breast-cancer risk. Most epidemiologic studies have involved Asian populations and some studies have shown a substantial reduction in breast-cancer risk (17-73%) in these populations. These results were also observed in countries where the level of consumption of traditional soy foods is low.

Topics: Asia; Breast Neoplasms; Estrogens, Non-Steroidal; Feeding Behavior; Female; Glycine max; Humans; Isoflavones; Phytoestrogens; Plant Preparations

This article is designed to help nursing professionals advise patients about the role of soy in the prevention and treatment of heart disease, breast cancer, and prostate cancer. Soy protein lowers total cholesterol, low-density lipoprotein cholesterol, and triglycerides in humans and inhibits atherosclerosis in animals. In cell culture studies and animal research, the soy isoflavone genistein offers protection from breast cancer and prostate cancer because it prevents cancer initiation, slows promotion, and impedes cancer progression. This article synthesizes the current research concerning soy phytoestrogens and the prevention and treatment of heart disease, breast cancer, and prostate cancer. Nursing professionals may use this information when counseling patients.

Topics: Animals; Arteriosclerosis; Breast Neoplasms; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Hypercholesterolemia; Isoflavones; Male; Patient Education as Topic; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; Soybean Proteins

Topics: Animals; Breast Neoplasms; Diet; Epidemiologic Studies; Estrogens; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Risk Factors

The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established.

Topics: Animals; Biomarkers; Breast Neoplasms; Case-Control Studies; Diet; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lignans; Phytoestrogens; Plant Preparations; Prospective Studies; Rats

Due to some severe side effects "classical" hormone replacement therapy (HRT) is currently being challenged by a therapy with phytoestrogens. Particularly soy and red clover derived isoflavones are advertised as selective estrogen receptor modulators (SERMs) with only desired and no undesired estrogenic effects. Evidence that this is the case however is scarce. Most studies investigating climacteric complaints did not find beneficial effects. A proposed beneficial effect on mammary cancer is unproven. The majority of studies however indicate an antiosteoporotic effect of isoflavones, while putative beneficial effects in the cardiovascular system are questionable due to the fact that estradiol which--like isoflavones--increase HDL and decrease LDL concentrations appear not to prevent arteriosclerosis in the human. In the urogenital tract, including the vagina, soy and red clover derived isoflavones are without effects. Cimicifuga racemosa extracts are traditionally used for the treatment of climacteric complaints. Evidence is now available that the yet unknown compounds in Cimicifuga racemosa extracts prevent climacteric complaints and may also have antiosteoporotic effects.

Topics: Bone and Bones; Breast Neoplasms; Cardiovascular System; Cimicifuga; Estrogens, Non-Steroidal; Female; Hormone Replacement Therapy; Humans; Isoflavones; Menopause; Osteoporosis; Phytoestrogens; Plant Extracts; Plant Preparations; Time Factors; Urogenital System

The way of nutrition and particular components of the diet have substantial influence on the development of many diseases. It has been proven by large epidemiological studies dealing with the incidence of cardiovascular diseases and tumours. What is more, the diet may have also an important role in the secondary prevention of myocardial infarction. The role of a soy as a component of the diet with potentially favorable action on human health was discussed in this paper. Special attention was paid to mechanisms of action of soy phytoestrogens and their influence on development of ischaemic heart disease, tumours, osteoporosis and other symptoms related to menopause.

Topics: Breast Neoplasms; Cardiovascular Diseases; Climacteric; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Male; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Soybean Proteins

Women frequently chose alternatives to hormone replacement therapy (HRT) for treatment of menopause even though medical indications for estrogens may be present. Prior breast cancer or fear of breast cancer is a major consideration. This review of alternatives to estrogen discusses the evidence linking breast cancer to HRTs and compares potential risks and benefits of HRT to nonHRT alternatives for relief of vasomotor symptoms, vaginal atrophy, neurocognitive changes and prevention of heart disease and osteoporosis. Practical guidelines are suggested for use of alternatives for each problem.

Topics: Aged; Antidepressive Agents; Atrophy; Bone Density; Bone Resorption; Breast Neoplasms; Calcitonin; Calcium; Cardiovascular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Contraindications; Diphosphonates; Double-Blind Method; Estrogen Replacement Therapy; Estrogens; Estrogens, Non-Steroidal; Female; Fractures, Bone; Hot Flashes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Isoflavones; Life Style; Menopause; Mental Disorders; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Osteoporosis, Postmenopausal; Phytoestrogens; Phytotherapy; Plant Preparations; Randomized Controlled Trials as Topic; Risk; Safety; Selective Estrogen Receptor Modulators; Urothelium; Vagina

Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism.

Topics: Breast Neoplasms; Estradiol; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Hydroxylation; Isoflavones; Neoplasms; Phytoestrogens; Plant Preparations; Postmenopause; Uterine Neoplasms; Vegetables

Breast cancer is the most common cancer among women and the leading cause of death in women, 40 to 55 years of age. The lifetime odds of developing breast cancer are apparently up to 1 in 8 women in North America and 1 in 12 in Western Europe. According to the American Cancer Society, some 200,000 women (and 1,500 men) will be diagnosed with breast cancer this year. Although the incidence of breast cancer in women has been rising since the mid-1940s, the mortality has dropped modestly over the past decade, probably due to earlier and improved diagnosis and treatment. Evidence from both epidemiological and experimental studies points to an important role of reproductive variables in the development and promotion of human breast neoplasia. Hormonal manipulations, in the form of contraceptives, hormone replacement therapy, or antiestrogens, affect the incidence and course of breast cancer and may be useful in prevention and treatment of the tumor. In this review we summarize the current status of the use of hormones and antihormones in regard to breast cancer and outline possible areas of additional development and investigation.. Obstetricians and Gynecologists, Family Physicians.. After completion of this article, the reader will be able to summarize the effects of estrogen and progestogens on the breast and to list the effects of other hormonal modulators on the breast.

Topics: Antineoplastic Agents; Breast Neoplasms; Contraceptives, Oral, Hormonal; Estrogens; Estrogens, Non-Steroidal; Female; Gonadotropin-Releasing Hormone; Hormone Replacement Therapy; Humans; Isoflavones; Melatonin; Phytoestrogens; Plant Preparations; Receptors, Estrogen

Phytoestrogens have been investigated at the epidemiological, clinical and molecular levels to determine their potential health benefits. The two major groups of phytoestrogens, isoflavones and lignans, are abundant in soy products and flax respectively, but are also present in a variety of other foods. It is thought that these estrogen-like compounds may protect against chronic diseases, such as hormone-dependent cancers, cardiovascular disease and osteoporosis. Furthermore, phytoestrogens are used as a natural alternative to hormone replacement therapy and to reduce menopausal symptoms. Phytoestrogens have been shown to induce both estrogenic and anti-estrogenic effects but their biological relevance and potency have not been well characterized. In children, consumption of soy-based formulas and soy milk can lead to high levels of exposure to phytoestrogens with only limited data available concerning potential benefits or adverse effects. Phytoestrogens are considered good candidates for use in natural therapies and as chemopreventive agents in adults. Safe and efficacious levels have yet to be established.

Topics: Biological Availability; Breast Neoplasms; Cardiovascular Diseases; Diet; Estrogens, Non-Steroidal; Female; Food Analysis; Humans; Isoflavones; Lignans; Male; Menopause; Osteoporosis; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms

Topics: Alcohol Drinking; Breast Neoplasms; Diet, Fat-Restricted; Estrogens, Non-Steroidal; Exercise; Female; Fruit; Health Promotion; Humans; Isoflavones; Male; Obesity; Phytoestrogens; Plant Preparations; Primary Prevention; Prostatic Neoplasms; Vegetables

Phyto-oestrogens have been suggested to have a preventive effect against various cancers. This review includes a discussion of the consumption of phyto-oestrogen-rich foods such as soy, a source of isoflavones, and whole grain products, which contain lignans, and their role in the prevention of breast, prostate, and colon cancer. In women, a soy-containing diet is only slightly protective against breast cancer, if at all, but is more likely to be beneficial if initiated before puberty or during adolescence. These findings are supported by conclusions of studies of immigrants and other epidemiological studies. However, in one case-control study and one prospective study, a low-lignan diet increased the risk of breast cancer. Experimental evidence also exists for an inhibitory effect of soy and rye bran on prostate-cancer growth and for rye bran or isolated lignans on colon cancer. Whether these observed protective effects are caused by the presence of dietary phyto-oestrogens, or whether they are merely indicators of a healthy diet in general, has not been established.

Topics: 4-Butyrolactone; Animals; Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lignans; Male; Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

Breast cancer is among the most common of the cancers that occur in women living in western societies. It is a much-feared disease and the risks are confusing and often badly reported. Oestrogen levels are a known risk factor. But is it possible to lower the risk? And where are all the oestrogens coming from?

Topics: Breast Neoplasms; Carcinogens, Environmental; Diet; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Xenobiotics

Estrogen replacement therapy (ERT) is recommended for postmenopausal women primarily for reduction of menopausal symptoms and prevention of osteoporosis and cardiovascular disease. However, only 35% to 40% of women ever start ERT, and many do not continue it. One of the reasons women are reluctant to receive postmenopausal ERT is that they perceive prescription estrogens as being "unnatural." Because of this, there is increasing interest in the use of plant-derived estrogens, also known as phytoestrogens. This article reviews the evidence for the potential of phytoestrogens, either in dietary or supplemental form, to replace traditional forms of ERT. A comprehensive search of the English-language literature identified more than 1000 articles published in the past 30 years about phytoestrogens. In total, 74 studies were selected for inclusion in this review based on relevance, inclusion of human subjects wherever possible, and study design. The studies examine phytoestrogens' inhibition of the growth of cancer cell lines in vitro and in animals. They also look at the role of phytoestrogens in the reduction of cholesterol levels, and the use of one phytoestrogen derivative, ipriflavone, in the prevention of osteoporosis. Some small studies examine the role of phytoestrogens in the prevention of menopausal symptoms. Evidence for the potential health benefits of phytoestrogens is increasing. However, the clinically proven health benefits of prescribed ERT far outweigh those of phytoestrogens. Therefore, there is insufficient evidence to recommend the use of phytoestrogens in place of traditional ERT, or to make recommendations to women about specific phytoestrogen products.

Topics: Breast Neoplasms; Cardiovascular Diseases; Cell Division; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Postmenopause; Prognosis

The current extension of the indications for adjuvant chemotherapy, which predisposes to early menopause, and the media coverage of the benefits of hormone replacement therapy (HRT) have led patients with a history of breast cancer to seek treatments for estrogen deprivation. In breast cancer survivors, most physicians avoid HRT because of concern regarding the potential promotion of growth of occult malignant cells by estrogens, due to the estrogen dependence of breast cancer. Soy phytoestrogens are being promoted as the 'natural alternative' to HRT and have been available without restrictions for several years as nutritional supplements. In this paper, data on the complex mammary effects of phytoestrogens in epidemiological studies, in in vitro studies, as well as in in vivo studies on animal carcinogenesis are reviewed. The potential benefits and risks of phytoestrogens are analyzed, and the prescription of phytoestrogens to postmenopausal women after breast cancer and the coprescription with the anti-estrogen tamoxifen are discussed. The absence of controlled trials and technical checking of extraction and titration in these preparations on 'free sale' raise a new problem in terms of public health and justify close reasoning and a cautious attitude of physicians, as well as straight information given to women, especially after breast cancer.

Topics: Animals; Breast; Breast Neoplasms; Clinical Trials as Topic; Contraindications; Dietary Supplements; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Glycine max; Hormone Replacement Therapy; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Tamoxifen

Organochlorine pesticides, including dichlorodiphenyltrichloroethane (DDT), are an environmental hazard due to their persistent nature and potential health effects. DDT and 1,1,dichloro-2,2,bis(p-chlorophenyl)ethylene (DDE) are lipid-soluble pesticides which accumulate in fatty tissues and are, therefore, more present in fat-containing foods such as meat, fish, milk, cheese and oil than in fruit, vegetables and grain. Scientists have for some time been concerned about the human exposure to DDT and the potential risk of breast cancer due to its oestrogenic activity. The introduction of foods containing chemopreventive agents in the diet could inhibit the oestrogenic effects of DDT and the risk of developing cancer. Phytooestrogens are weak oestrogens found in certain plants such as soybean. They compete with DDT for oestrogen receptors and inhibit the oestrogenic effect of DDT on cultured human breast (MCF) cells. Curcumin, a spice widely used in Indian dishes, has anti-carcinogenic and anti-inflammatory properties. It also inhibits the oestrogenic effects of DDT and is synergistic with phytooestrogens. Indole-3-carbinol, a compound naturally found in cruciferous vegetables, stimulates oestrogen metabolism towards 2-hydroxyoestrone which reduces the oestrogenic response in MCF cells and the risk of breast cancer. Since DDT is lipid soluble and accumulates in adipose tissue it could have a role in lipid metabolism. Would a low fat diet reduce DDT bioaccumulation? A reduction in calories can decrease oestrogen levels and possibly reduce the risk of breast cancer. A dietary modification with the introduction of soy products, curcumin, cruciferous vegetables and low fat could be beneficial in reducing the risk of developing cancer and possibly the effects of DDT.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Carcinogens; DDT; Dietary Fats; Environmental Exposure; Estrogens, Non-Steroidal; Feeding Behavior; Female; Food Contamination; Health Behavior; Humans; Insecticides; Isoflavones; Phytoestrogens; Plant Preparations; United Kingdom

Topics: Breast Neoplasms; Endometrial Neoplasms; Epidemiologic Studies; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Lung Neoplasms; Male; Neoplasms; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors; Stomach Neoplasms

Phytoestrogens, plant chemicals classified as isoflavones, coumestans and lignans, display estrogen-like activity because of their structural similarity to human estrogens and exhibit high affinity binding for the estrogen receptor beta. They are common components of food items such as grains, beans, fruits and nuts. Isoflavones are primarily found in soybeans and foods made from soy. In particular, significant therapeutic properties have been generally attributed to soy isoflavones, but most of the claims have been poorly, or not at all, confirmed by well designed clinical trials. Such is the case of the purported role of soy isoflavones in reducing plasma cholesterol levels. This link is now not supported by many authors or by appropriately designed clinical studies. The role of isoflavones in cancer prevention, particularly of tumours under endocrine control (breast, prostate and others) is again only supported by weak to nonexisting clinical evidence. A similarcase is that of the prevention/treatment of postmenopausal symptoms and osteoporosis. Disturbing data have been reported on potential negative effects of soy isoflavones on cognitive function in the aged, particularly relating to tofu intake. Recent studies have finally indicated a potential role for soy isoflavones in inducing chromosomal changes in cells exposed in vitro and potentiating chemical carcinogens. These findings may not, however, be extrapolated to clinical conditions. Available data do not appear to unequivocally support beneficial effects of soy isoflavones, and warn against their wide use, in the absence of satisfactory clinical findings.

Topics: Adult; Animals; Breast Neoplasms; Cardiovascular Diseases; Cholesterol; Climacteric; Cognition; Diet; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Soybean Proteins

To determine whether genistein and daidzein, the major phytoestrogens in soy, can stimulate breast cancer growth.. Systematic search through primary English-language literature on MEDLINE (1966-January 2001), EMBASE (1982-January 2001) and Current Contents (1998-January 2001).. Genistein and daidzein at low concentrations were found to stimulate breast tumor growth in in vitro and in vivo animal studies, and antagonize the antitumor effect of tamoxifen in vitro. At high concentrations, genistein inhibited tumor growth and enhanced the effect of tamoxifen in vitro.. Genistein and daidzein may stimulate existing breast tumor growth and antagonize the effects of tamoxifen. Women with current or past breast cancer should be aware of the risks of potential tumor growth when taking soy products.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Soybean Proteins; Tamoxifen

Topics: Bone Density; Breast Neoplasms; Cholesterol; Estrogens, Non-Steroidal; Female; Hormone Replacement Therapy; Hot Flashes; Humans; Isoflavones; Menopause; Osteoporosis; Phytoestrogens; Plant Preparations; Soybean Proteins

Topics: Animals; Bone Density; Breast Neoplasms; Cognition; Coronary Disease; Endometrial Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Osteoporosis; Patient Compliance; Phytoestrogens; Plant Preparations; Risk Assessment; Soybean Proteins; Treatment Outcome

This review is a summary of three reference books and of the final report of a European concerted action. The data have been updated by an analysis of recent publications, according to the same methodological criteria as those used in the reference books: sample size, quality of questionnaire and statistical methods. Mechanistic hypothesis are considered for each microcompounds, the effect of which is situated along the natural history of cancer. Few studies have considered folates effect on breast cancer, and they observed an interaction with the risk related to alcohol consumption, which is decreased with a high intake of folates. Many studies considered the effect of vitamin C and E, and carotenoids, but results are inconsistent. Conflicting results were also observed in studies on fibre and breast cancer. However, although only half of the studies showed a protective effect, the strength of the biological mechanisms give support to the hypothesis of a protection provided by fibre. The situation is comparable with phyto-estrogens: epidemiological studies are scarce and few of them show significant protection, but several plausible biological mechanisms are proposed, either related to the negative modulation of estrogen receptor by phyto-estrogen, or to the inhibition of proliferation by action on various enzymes. At the present time, caution in the interpretation of the results and in the use of plant microcompounds in prevention or therapy is strongly recommended.

Topics: Antioxidants; Ascorbic Acid; Breast Neoplasms; Diet; Dietary Fiber; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Vegetables; Vitamin E

The steroid hormone estrogen influences female and male reproductive system, 17-beta-oestradiol is the major human oestrogen. Phytoestrogens are naturally occurring oestrogens in many foods of plant origin. They are structurally and functionally similar to 17-beta-oestradiol or produce estrogenic effects. It is suggested that phytoestrogens could lower risk of diseases accompanied woman in meno- and postmenopausal stage. They are consider to decrease risk of breast, endometrial and ovarian cancer, osteoporosis, cardiovascular disease. This report presents the literature review on nutritious and health aspects connected with phytoestrogens. Generally authors confirm the possibility of beneficial health effects of phytoestrogens in humans.

Topics: Age Factors; Breast Neoplasms; Cardiovascular Diseases; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Osteoporosis; Ovarian Neoplasms; Phytoestrogens; Plant Preparations; Plants, Edible; Time Factors; Uterine Neoplasms

There is clearly a need for novel breast cancer chemopreventive agents with enhanced potency and specificity with little or no side effects. To this end, several new chemical moieties have been synthesized or isolated from natural sources. In this review, we have described some agents currently in use or under development for treatment or prevention of breast cancer, as well as our own strategies for the discovery of natural product modulators of estrogen biosynthesis and function. In particular, bioassay-guided fractionation of active plant extracts is a unique method for identifying agents with novel mechanisms of action, some of which should be useful for prevention of human cancer. Further, with the advent of combinatorial chemistry and high throughput screening, even greater progress may now be expected with natural product leads.

Topics: Anticarcinogenic Agents; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Selective Estrogen Receptor Modulators; Sulfatases

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations

Topics: Alcohol Drinking; Breast Neoplasms; Carcinogens; Carcinoma; Diet; Dietary Fats; Estrogens, Non-Steroidal; Ethnicity; Fatty Acids; Feeding Behavior; Female; Fruit; Humans; Isoflavones; Meat; Phytoestrogens; Plant Preparations; Plants; Racial Groups; Risk Factors; Vegetables

Due to the improving life expectancy of women spend third of their active life after the menopause. Estrogen deficiency can be caused by both natural and artificial menopause. The lack of estrogen can directly worsen the quality of life and epidemiological evidence suggests association with development of certain diseased states. Hormone replacement with natural estrogens has been proven to be successful for various indications: it reduces the menopausal vasomotor and psychological symptoms thus improving quality of life. It can also be used to prevent harmful effects of estrogen deficiency in various organs. Literature review supports the role of estrogen in atherosclerosis and osteoporosis prevention. Further evidence required establishing the role of estrogens in secondary prevention of coronary artery disease. Also needs to be explained why the beneficial effects of estrogen therapy in osteoporosis seem to disappear soon after cessation of therapy. Currently the relative risk increase of breast cancer during long-term hormone replacement therapy cannot be exactly measured. Nevertheless, substantial reduction of mortality in estrogen receptor positive breast cancer can also be seen with women on hormone replacement as compared to controls. Some data support the negative correlation of residual but still detectable, endogen estrogen and atherosclerosis and similarly to osteoporosis. The same residual estrogen levels seem to correlate positively with breast cancer. The recognition (and further acceptance) of the role of the residual estrogens might have influence on the indication, choice and dosage of preparation and duration of hormone replacement therapy. Overall evidence is in favor of the need medical attention for menopause: which ranges from preventive screening to long term hormone replacement therapy. The decision to treat requires the risks and benefits taken into consideration. This highly specialized care is provided in menopause clinics in Hungary. New oestrogen like agents are being developed like the selective estrogen receptor modulators, the tibolone and the phyto-estrogens. They provide tissue-specific effect acting as estrogen agonistics, sustaining the beneficial preventive and therapeutic effects of the estrogens, but in the breast and endometrial tissue they behave like estrogen antagonists avoiding the side effects of the current used oestrogens. They might play a significant role in the treatment of menopause in the future.

Topics: Breast Neoplasms; Cardiovascular Physiological Phenomena; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations; Selective Estrogen Receptor Modulators

Topics: Breast Neoplasms; Estrogen Antagonists; Estrogens, Non-Steroidal; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants, Medicinal

With the advent of screening and the increased incidence of breast cancer, concern for the prevention of breast cancer has become forefront in today's society. Determining individual risk is the key to prescribing prevention. Prevention of breast cancer is still under clinical investigation with only one drug, tamoxifen, showing benefit in high risk patients. This paper reviews the possible sites for prevention of neoplastic transformation via biomarkers in a breast cell as well as the investigational drugs and their potential use in the chemoprevention of breast cancer.

Topics: Adult; Aged; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Apoptosis; Biological Products; Breast Neoplasms; Breast Neoplasms, Male; Carotenoids; Cathepsin D; Cell Adhesion Molecules; Cell Cycle; Clinical Trials, Phase III as Topic; Drug Screening Assays, Antitumor; Estrogens, Non-Steroidal; Female; Fenretinide; Genetic Predisposition to Disease; Hormone Antagonists; Humans; Isoflavones; Male; Mammary Neoplasms, Experimental; Mastectomy; Mice; Middle Aged; Neovascularization, Pathologic; Ovariectomy; Phytoestrogens; Plant Preparations; Raloxifene Hydrochloride; Rats; Retinoids; Risk Assessment; Risk Factors; Selenium; Tamoxifen; Terpenes

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Contraindications; Estrogens, Non-Steroidal; Female; Hormone Replacement Therapy; Humans; Isoflavones; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Risk Factors

Despite the use of currently available drug therapies, the life expectancy of patients with metastasized breast cancer can still only be extended by about 14 to 16 months in comparison to a completely untreated patient population. In light of these figures, and the associated economic costs, all possible means to reduce the incidence of the disease are of great potential importance and must be examined seriously.. Increased consumption of alcohol is a risk factor for breast cancer. Increased intake of phytoestrogens, dietary fiber, and beta-carotene as well as regular physical activity and normal body weight lower the risk of breast cancer. The increased risk of breast cancer associated with alcohol consumption can be reduced by adequate intake of folate. The significance of retinoids is at present ambiguous.. Effective preventive measures, along with adequate early detection schemes, are the best means of reducing mortality due to breast cancer. Both folate and retinoids deserve to be subjected to further studies. It would also be desirable to supplement currently ongoing adjuvant therapy trials with studies examining the use of folate versus placebo.

Topics: Anticarcinogenic Agents; beta Carotene; Breast Neoplasms; Cohort Studies; Diet; Dietary Fiber; Estrogens, Non-Steroidal; Exercise; Female; Folic Acid; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Primary Prevention; Risk Factors; Temperance

Topics: Adult; Aged; Alzheimer Disease; Breast Neoplasms; Cardiovascular Diseases; Cohort Studies; Diet; Double-Blind Method; Embryonal Carcinoma Stem Cells; Estrogens; Estrogens, Non-Steroidal; Female; Follow-Up Studies; Gonadal Steroid Hormones; Hormone Replacement Therapy; Hot Flashes; Humans; Isoflavones; Longevity; Menopause; Menopause, Premature; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Neoplasms, Second Primary; Neoplastic Stem Cells; Obesity; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Randomized Controlled Trials as Topic; Safety; Selective Estrogen Receptor Modulators; Survivors; Weight Gain

Phytoestrogens, such as the soya isoflavones genistein and daidzein, are currently being extensively investigated through both molecular, preclinical and clinical studies to determine their potential health benefits. Phytoestrogens may protect against chronic diseases such as hormone-dependent cancer (e.g., breast and prostate cancer), cardiovascular disease and osteoporosis. Investigations of phytoestrogen metabolism and bioavailability are also of great relevance. Conversion by gut microflora of daizein to its isoflavan metabolite equol, which is a more potent oestrogen and anti-oxidant, occurs only in some individuals (about 35% of subjects tested are equol excretors). This has considerable implications for daidzein bioavailability and also for cancer risk. Oxidative damage has been implicated in the development of heart disease and cancer and soya phytoestrogens have been reported to decrease plasma F(2)-isoprostane concentrations (biomarker for in vivo lipid peroxidation) and increase low density lipoprotein oxidation resistance. This anti-oxidant action of phytoestrogens could potentially contribute to their therapeutic efficacy. The findings from the current ongoing studies are all likely to contribute to determining the potential use of phytoestrogens as therapeutic agents.

Topics: Animals; Anticarcinogenic Agents; Breast Neoplasms; Cardiovascular Diseases; Diet; Estrogens, Non-Steroidal; Humans; Isoflavones; Phytoestrogens; Plant Preparations

Isoprene is the main component of steroid hormones. It is found in many plants and herbal compounds, e.g. the isoflavonoids are therefore slightly estrogenic. Since they are bound to the estradiol receptors, more active estrogens cannot induce a signal transduction. Hence phytoestrogens may be protective on breast tissue and other hormone dependent organs.

Topics: Aged; Anticarcinogenic Agents; Breast Neoplasms; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Postmenopause; Receptors, Estrogen; Resveratrol; Selective Estrogen Receptor Modulators; Stilbenes

Topics: 4-Butyrolactone; Animals; Breast Neoplasms; Edible Grain; Estrogens; Estrogens, Non-Steroidal; Female; Finland; Food; Humans; Isoflavones; Japan; Lignans; Phytoestrogens; Plant Preparations; Pregnancy; Prenatal Exposure Delayed Effects

Topics: Antioxidants; Breast Neoplasms; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Risk Factors

Topics: Animals; Breast Neoplasms; Digestive System; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Hydrolysis; Isoflavones; Oxidation-Reduction; Phytoestrogens; Plant Preparations

Topics: Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Kidney Failure, Chronic; Milk, Human; Phytoestrogens; Plant Preparations; Renal Dialysis; Risk Factors

Population-based studies from around the world support the theory that soy products and their constituents, primarily the isoflavones or phytoestrogens, are partly responsible for the lower rates of certain chronic diseases in different areas of the world. Cardiovascular disease and hormonally induced cancers are just a few of the conditions lower in Asian countries that consume large quantities of soy per average person. Genistein, one of soy's individual phytoestrogens, has been found to inhibit numerous breast and prostate cancer cell lines. A limited amount of clinical evidence also points to a beneficial role of soy in reducing hormonal levels and exhibiting weak estrogen and antiestrogen-like qualities. Other phytoestrogens found in nature, such as lignans, may also have a future role in cancer. Collectively, these phytoestrogens, like genistein, have enough evidence to warrant their use in a number of clinical trials as a potential chemopreventive agent or adjunct to prostate cancer treatment.

Topics: Breast Neoplasms; Cardiovascular Diseases; Chemoprevention; Chronic Disease; Epidemiologic Methods; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Male; Phytoestrogens; Phytotherapy; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

Topics: Breast Neoplasms; Cardiovascular Diseases; Clinical Trials as Topic; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Osteoporosis; Phytoestrogens; Piperidines; Plant Preparations; Raloxifene Hydrochloride; Receptors, Estrogen; Survivors

Phytoestrogens are diphenolic compounds that are present in several plants eaten by human beings. Soybeans and flaxseed are particularly abundant source of phytoestrogens. When ingested in relatively large amounts, phytoestrogens have been shown to have significant estrogen agonists/antagonists effects in animals and humans. There is epidemiological, laboratory and clinical evidence which indicates that phytoestrogens, like certain selective estrogen receptor mudulators, have an antiproliferative effect on the breast, and positive effects on the lipoprotein profile and bone density. They might also improve some of the climacteric symptoms. This evidence is critically reviewed, and the possible benefit of dietary intervention with phytoestrogen-rich food for woman's health is discussed.

Topics: Breast Neoplasms; Diet; Estrogens, Non-Steroidal; Female; Flax; Glycine max; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations; Receptors, Estrogen

Women in the United States are increasingly turning to botanical medicines to treat conditions throughout their life cycles. Many herbs traditionally used for women's health conditions have been found to contain phytoestrogens. Phytoestrogens and their metabolites can bind estrogen receptors and can have both estrogenic and anti-estrogenic effects. Many women are attracted to the idea of using phytomedicine as an alternative to hormone replacement therapy. It is unclear, however, whether these herbs are safe for women at risk for breast cancer or its recurrence. This paper considers the estrogenicity of herbs such as black cohosh (Cimicifuga racemosa) and the implications for women's health.

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Phytotherapy; Plant Preparations; Receptors, Estrogen; United States; Women's Health

This review will focus on antioestrogens and selective oestrogen receptor modulators (SERMS). The more traditional SERMS, clomiphene citrate and tamoxifen, will be reviewed along with such modern drugs as raloxifene and faslodex, with emphasis upon their actions on breast, uterus, bone and lipids. The future potential of these medications, in the management of oestrogen-dependent gynaecological conditions such as endometriosis, dysfunctional uterine bleeding, fibroids and breast cancer will be discussed.

Topics: Bone and Bones; Breast Neoplasms; Clomiphene; Estradiol; Estrogen Receptor Modulators; Estrogens, Non-Steroidal; Female; Fulvestrant; Genital Diseases, Female; Humans; Isoflavones; Osteoporosis; Phytoestrogens; Plant Preparations; Plants; Raloxifene Hydrochloride; Selective Estrogen Receptor Modulators; Tamoxifen; Women's Health

Although there is evidence that phytochemicals decrease the incidence of breast and endometrial cancer, many observations are only phenomenologic, and much work needs to be done to explore basic mechanisms and the strategic exploitation of their interactions. The multiplicity of phytochemical actions at different sites in the process of tumorigenesis may eventually lead to the development of a multiagent strategy designed to maximize the complementary effects of different agents. A number of effects with possible relevance to cancer chemoprevention have been excluded from this review, including effects of phytochemicals on the immune response; the question of dietary restriction, which has a profound effect on tumorigenesis; the relatively low methionine levels in some phytochemicals such as soy, which may limit the synthesis of polyamines necessary for tumor growth [151]; and the fact that diets higher in plant products are usually lower in fat and result in leaner individuals with less potential for the synthesis of estradiol in adipose tissue. Also, many studies dealing solely with in vitro mutagenesis were excluded.

Topics: Amino Acid Sequence; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Antioxidants; Apoptosis; Breast Neoplasms; Carotenoids; Cell Differentiation; Diet; Endometrial Neoplasms; Enzyme Inhibitors; Estrogens, Non-Steroidal; Ethnicity; Female; Gene Expression Regulation; Growth Inhibitors; Humans; Isoflavones; Molecular Sequence Data; Phytoestrogens; Plant Preparations; Plants, Edible; Terpenes

Epidemiological studies suggest that diets rich in phytoestrogens (plant estrogens), particularly soy and unrefined grain products, may be associated with low risk of breast and prostate cancer. It has also been proposed that dietary phytoestrogens could play a role in the prevention of other estrogen-related conditions, namely cardiovascular disease, menopausal symptoms and post-menopausal osteoporosis. However, there is no direct evidence for the beneficial effects of phytoestrogens in humans. All information is based on consumption of phytoestrogen-rich diets, and the causal relationship and the mechanisms of phytoestrogen action in humans still remain to be demonstrated. In addition, the possible adverse effects of phytoestrogens have not been evaluated. It is plausible that phytoestrogens, as any exogenous hormonally active agent, might also cause adverse effects in the endocrine system, i.e. act as endocrine disrupters.

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Diet; Endocrine Glands; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Receptors, Estrogen

Phytoestrogens are paradoxical. Because of their structural similarity to the physiological oestrogens, they have been assumed to increase the risk of breast cancer. However, nations where the largest amounts of phytoestrogens are consumed in the diet have the lowest incidence of and rate of death from breast cancer. Although these epidemiological observations do not prove that phytoestrogens have anti-cancer properties, many preclinical experiments support this concept. Some indicate that early life exposure to phytoestrogens may be critical for breast cancer prevention. Clinical studies to define the effect of phytoestrogens on breast cancer recurrence are underway. The recent discovery of a second class of oestrogen receptors, with a differential distribution among the tissues, may enable an explanation of the phytoestrogen paradox. These receptors have opened a way of utilizing phytoestrogens in the treatment of oestrogen-sensitive chronic diseases such as atherosclerosis and osteoporosis.

Topics: Animals; Breast Neoplasms; Diet; Estrogens; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Phytoestrogens; Plant Preparations

Epidemiological studies have revealed that high levels of lignans and isoflavonoids are frequently associated with low breast, prostate and colon cancer risk, as well as a low risk of coronary heart disease. These compounds seem to be cancer protective and/or are biomarkers of a 'healthy' diet. All soy protein products consumed by Asian populations have high concentrations of isoflavonoids. In other countries, such as Finland and Sweden, the lignan levels are higher in populations with the lowest risk because of a high consumption of whole-grain rye bread, berries and some vegetables. There is a strong association between fibre intake per kilogram body weight and lignan concentrations in body fluids. Breast cancer has been found to be associated with low lignan levels in the USA, Finland, Sweden and Australia. With regard to prostate and colon cancer, as well as coronary heart disease, the epidemiological data related to phytoestrogens are still very limited.

Topics: Breast Neoplasms; Coronary Disease; Diet; Epidemiology; Estrogens, Non-Steroidal; Humans; Isoflavones; Lignans; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms

Women are exposed to xenobiotic estrogens at least to the same extent as men. These estrogenic chemicals are either from plant material in the diet (phytoestrogens) or from industrial sources. Mainly industrially derived environmental estrogens may accumulate within the food chain and persist in human adipose tissue. In contrast, phytoestrogens do not bioaccumulate and are rapidly excreted in urine. The phytoestrogens probably represent the source of most extensive exposure for humans. Epidemiological evidence suggests that diets rich in phytoestrogens are associated with reduced incidences of cardiovascular disease, breast cancer, prostate cancer and osteoporosis. The numerous bioactivities (other than just estrogenicity) of phytoestrogens and related dietary compounds make it difficult to single out the mechanisms mediating such protective effects. The possibility that the newly discovered estrogen receptor beta may be an important modulator of phytoestrogen action is opening up new lines of research. While the evidence suggests that phytoestrogens may be of positive relevance to postmenopausal women, indications that exposure of women to industrially derived xenobiotic estrogens provides risks to health remain unproven. Further work is necessary to clarify the relative importance of 'xenobiotic' estrogens to human health, but it must be emphasized that the estrogenic potency of all the xenobiotic estrogens is very low compared with that of endogenous estrogens.

Topics: Breast Neoplasms; Cardiovascular Diseases; Diet; Environmental Exposure; Environmental Pollutants; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Risk Factors

Many substances are active in in vitro tests for estrogenic activity, but data from multigenerational and other toxicity studies are not available for many of those substances. Controversy has arisen, therefore, concerning the likelihood of adverse health effects. Based on a toxic equivalence factor risk assessment approach, some researchers have concluded that exposure to environmental estrogens is not associated with estrogen receptor (ER)-mediated health effects. Their rationale cites the low potency of these compounds in in vitro assays relative to estradiol, and the widespread exposure to pharmaceutical, endogenous, and dietary estrogens. This reasoning relies on two assumptions: that the relative estrogenic potency in in vitro assays is predictive of the relative potency for the most sensitive in vivo estrogenic effect; and that all estrogens act via the same mechanism to produce the most sensitive in vivo estrogenic effect. Experimental data reviewed here suggest that these assumptions may be inappropriate because diversity in both mechanism and effect exists for estrogenic compounds. Examples include variations in ER-ligand binding to estrogen response elements, time course of nuclear ER accumulation, patterns of gene activation, and other mechanistic characteristics that are not reflected in many in vitro assays, but may have significance for ER-mediated in vivo effects. In light of these data, this report identifies emerging methodological issues in risk assessment for estrogenic compounds: the need to address differences in in vivo end points of concern and the associated mechanisms; pharmacokinetics; the crucial role of timing and duration of exposure; interactions; and non-ER-mediated activities of estrogenic compounds.

Topics: Animals; Breast Neoplasms; Drug Evaluation, Preclinical; Environmental Exposure; Environmental Health; Environmental Pollutants; Estrogens; Estrogens, Non-Steroidal; Female; Humans; In Vitro Techniques; Isoflavones; Male; Phytoestrogens; Plant Preparations; Pregnancy; Receptors, Estrogen; Risk Assessment

Topics: Animals; Breast Neoplasms; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Mammary Neoplasms, Experimental; Phytoestrogens; Plant Preparations; Plants; Receptors, Estrogen; Stimulation, Chemical; Structure-Activity Relationship

To the extent that diet is involved in the etiology of breast cancer, its effect may be mediated, in part, through hormonal mechanisms. It has been suggested that the consumption of phytoestrogens is related inversely to breast cancer risk. Phytoestrogens are weak estrogens of plant derivation that may have antiestrogenic effects through competitively binding to estrogen receptors, thus diminishing the binding of stronger endogenous estrogens. This paper advances the hypothesis that, through this mechanism, dietary phytoestrogens may attenuate the adverse consequences of obesity on the development of postmenopausal breast cancer. Such an association might partly explain the low breast cancer rates observed among postmenopausal Hispanic women despite their greater adiposity, an important breast cancer risk factor. This hypothesis would lead us to expect that obesity increases the risk of postmenopausal breast cancer in women consuming small quantities of phytoestrogens but does not increase risk in women consuming larger quantities. If the hypothesis is confirmed, such as association could have important implications for reducing breast cancer risk through diet, using naturally occurring substances, particularly in women for whom postmenopausal obesity is an important health concern.

Topics: Body Composition; Breast Neoplasms; Diet; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Female; Hispanic or Latino; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Obesity; Phytoestrogens; Plant Preparations; Plants; Postmenopause; Receptors, Estrogen; Risk Factors

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Diet, Vegetarian; Dietary Fats; Dietary Fiber; Endometrial Neoplasms; Estrogens; Estrogens, Non-Steroidal; Female; Gonadal Steroid Hormones; Humans; Incidence; Isoflavones; Lignans; Lignin; Male; Menopause; Ovarian Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Risk Factors

It is a general opinion that the Western diet plays a significant role in increasing the risk of breast cancer in the Western World. Recently some likely mechanisms involved in increasing the risk have been disclosed. It has been found that a Western-type diet elevates plasma levels of sex hormones and decreases the sex hormone binding globulin concentration, increasing the availability of these steroids for peripheral tissues. The same diet results in low formation by intestinal bacteria of mammalian lignans and isoflavonoid phyotestrogens from plant precursors. These diphenolic compounds seem to affect hormone metabolism and production and cancer cell growth by many different mechanisms making them strong candidates for a role as cancer protective substances. The sex hormone pattern found in connection with a Western-type diet combined with low lignan and isoflavonoid excretion was found particularly in postmenopausal breast cancer patients and omnivores living in high-risk areas, and to a lesser degree in areas with less risk. However, the pattern observed was not entirely due to diet.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Diet; Dietary Fats; Dietary Fiber; Dietary Proteins; Estrogens; Estrogens, Non-Steroidal; Feces; Feeding Behavior; Female; Humans; Isoflavones; Lignans; Lignin; Phytoestrogens; Plant Preparations; Sex Hormone-Binding Globulin

A brief account of our present knowledge on the enterohepatic metabolism of estrogens and on the origin, metabolism and biological effects of mammalian lignans and phytoestrogens is undertaken. Furthermore, recently published results on the effects of dietary fiber, fat and carbohydrates on estrogen metabolism are reviewed. New preliminary results are presented on quantitative assays of lignans and phytoestrogens in urine of women belonging to various dietary and population groups and in a group of chimpanzees. The highest values of lignans and phytoestrogens were found in the non-human primates, and in macrobiotic, lactovegetarian and Japanese women, all groups considered having a low risk for the development of breast and other hormone-dependent cancer. New results on correlations between intake of various fibers, lignan and phytoestrogen excretion and plasma levels of estrogens, free testosterone and SHBG in women are presented. There is a significant positive correlation between the intake of fiber and urinary excretion of lignans and phytoestrogens, and the concentration of plasma SHBG. Fiber intake and urinary excretion of lignans and equol correlated negatively with plasma percentage free estradiol. Enterolactone excretion correlated negatively with plasma free testosterone. It is concluded that dietary macro- and micronutrients seem to play an important role in estrogen metabolism.

Topics: Animals; Bile; Breast Neoplasms; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Dietary Proteins; Enterohepatic Circulation; Estrogens; Estrogens, Non-Steroidal; Humans; Intestinal Mucosa; Isoflavones; Lignans; Liver; Phytoestrogens; Plant Extracts; Plant Preparations; Sex Hormone-Binding Globulin

Equol, a nonsteroidal estrogen of dietary origin, was recently identified in human urine, and is excreted in amounts comparable to the classical steroidal estrogens. We confirm here that phytoestrogens which are abundant in dietary soya protein are converted by human gastrointestinal flora to this weak estrogen. After the ingestion of meals containing cooked soya protein the urinary excretion of equol in four of six subjects studied increased by up to 1000-fold and this compound was the major phenolic compound found in the urine. These data also indicate that some subjects are unable to either produce or excrete equol despite the challenge of a diet containing soya. In view of the increasing use of commercial soya products in the diet and the capacity of human bacterial flora to synthesize this weak estrogen from the abundance of phytoestrogens in soya, the potential relevance of these observations to the diseases implicating steroid hormones is discussed.

Topics: Adult; Bacteria; Benzopyrans; Breast Neoplasms; Chromans; Diet; Dietary Proteins; Digestive System; Equol; Estrogens; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Male; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Risk

Unprecedented community containment measures were taken following the recent outbreak of COVID-19 in Italy. The aim of the study was to explore the self-reported future compliance of citizens with such measures and its relationship with potentially impactful psychological variables.. An online survey was completed by 931 people (18-76 years) distributed across the Italian territory. In addition to demographics, five dimensions were measured: self-reported compliance with containment measures over time (today, at 7, 14, 30, 60, 90, and 180 days from now) at three hypothetical risk levels (10, 50, 90% of likelihood of contracting the COVID-19), perceived risk, generalized anxiety, intolerance of uncertainty, and relevance of several psychological needs whose satisfaction is currently precluded.. The duration of containment measures plays a crucial role in tackling the spread of the disease as people will be less compliant over time. Psychological needs of citizens impacting on the compliance should be taken into account when planning an easing of the lockdown, along with interventions for protecting vulnerable groups from mental distress.. La apendicitis aguda (AA) es la urgencia quirúrgica abdominal más frecuente. No encontramos estudios específicos que evalúen el impacto de la pandemia causada por el coronavirus 2 (SARS-Cov-2) sobre la AA y su tratamiento quirúrgico. Analizamos la influencia de esta nueva patología sobre la AA.. Estudio observacional retrospectivo en pacientes intervenidos por AA desde enero hasta abril de 2020. Fueron clasificados según el momento de la apendicectomía, antes de la declaración del estado de alarma (Pre-COVID19) y después de la declaración del estado de alarma (Post-COVID19) en España. Se evaluaron variables demográficas, duración de la sintomatología, tipo de apendicitis, tiempo quirúrgico, estancia hospitalaria y complicaciones postoperatorias.. La pandemia por SARS-Cov-2 influye en el momento de diagnóstico de la apendicitis, así como en su grado de evolución y estancia hospitalaria. La peritonitis fue lo más frecuentemente observado. Una sospecha y orientación clínica más temprana, es necesaria para evitar un manejo inadecuado de este trastorno quirúrgico común.. The primary outcome is improvement in PaO. Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).. None.. The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies.. La surveillance de l’intervalle QT a suscité beaucoup d’intérêt durant la pandémie de la COVID-19 en raison de l’utilisation de médicaments prolongeant l’intervalle QT et les préoccupations quant à la transmission virale par les électrocardiogrammes (ECG) en série. Nous avons posé l’hypothèse que la surveillance en continu de l’intervalle QT par télémétrie était associée à une meilleure détection des épisodes de prolongation de l’intervalle QT.. Nous avons introduit la télémétrie cardiaque en continu (TCC) à l’aide d’un algorithme de surveillance automatisée de l’intervalle QT dans nos unités de COVID-19. Les mesures automatisées quotidiennes de l’intervalle QT corrigé (auto-QTc) en fonction de la fréquence cardiaque maximale ont été enregistrées. Nous avons comparé la proportion des épisodes de prolongation marquée de l’intervalle QTc (QTc long), définie par un intervalle QTc ≥ 500 ms, chez les patients montrant une suspicion de COVID-19 ou ayant la COVID-19 qui avaient été admis avant et après la mise en place de la TCC (groupe témoin. La surveillance en continu de l’intervalle QT est supérieure à la norme de soins dans la détection des épisodes de QTc long et exige peu d’ECG. La réponse clinique aux épisodes de QTc long est sous-optimale.. Exposure to a model wildfire air pollution source modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.. Though the majority of HIV-infected adults who were on HAART had shown viral suppression, the rate of suppression was sub-optimal according to the UNAIDS 90-90-90 target to help end the AIDS pandemic by 2020. Nonetheless, the rate of immunological recovery in the study cohort was low. Hence, early initiation of HAART should be strengthened to achieve good virological suppression and immunological recovery.. Dust in Egyptian laying hen houses contains high concentrations of microorganisms and endotoxins, which might impair the health of birds and farmers when inhaled. Furthermore, laying hens in Egypt seem to be a reservoir for ESBL-producing Enterobacteriaceae. Thus, farmers are at risk of exposure to ESBL-producing bacteria, and colonized hens might transmit these bacteria into the food chain.. The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.. Most comparisons for different outcomes are based on very few studies, mostly low-powered, with an overall low CoE. Thus, the available evidence is considered insufficient to either support or refute CH effectiveness or to recommend one ICM over another. Therefore, further well-designed, larger RCTs are required.. PROSPERO database Identifier: CRD42016041953.. Untouched root canal at cross-section perimeter, the Hero 642 system showed 41.44% ± 5.62% and Reciproc R40 58.67% ± 12.39% without contact with instruments. Regarding the untouched area, Hero 642 system showed 22.78% ± 6.42% and Reciproc R40 34.35% ± 8.52%. Neither instrument achieved complete cross-sectional root canal debridement. Hero 642 system rotary taper 0.02 instruments achieved significant greater wall contact perimeter and area compared to reciprocate the Reciproc R40 taper 0.06 instrument.. Hero 642 achieved higher wall contact perimeter and area but, regardless of instrument size and taper, vital pulp during. The functional properties of the main mechanisms involved in the control of muscle Ca. This study showed that the anti-inflammatory effect of the iron-responsive product DHA in arthritis can be monitored by an iron-like radioactive tracer (. Attenuated vascular reactivity during pregnancy suggests that the systemic vasodilatory state partially depletes nitric oxide bioavailability. Preliminary data support the potential for MRI to identify vascular dysfunction in vivo that underlies PE. Level of Evidence 2 Technical Efficacy Stage 1 J. MAGN. RESON. IMAGING 2021;53:447-455.. La evaluación de riesgo es importante para predecir los resultados postoperatorios en pacientes con cáncer gastroesofágico. Este estudio de cohortes tuvo como objetivo evaluar los cambios en la composición corporal durante la quimioterapia neoadyuvante e investigar su asociación con complicaciones postoperatorias. MÉTODOS: Los pacientes consecutivos con cáncer gastroesofágico sometidos a quimioterapia neoadyuvante y cirugía con intención curativa entre 2016 y 2019, identificados a partir de una base de datos específica, se incluyeron en el estudio. Se utilizaron las imágenes de tomografía computarizada, antes y después de la quimioterapia neoadyuvante, para evaluar el índice de masa muscular esquelética, la sarcopenia y el índice de grasa visceral y subcutánea.. In this in vitro premature infant lung model, HF oscillation of BCPAP was associated with improved CO. Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.. Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis.. These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.

Topics: 3T3-L1 Cells; A Kinase Anchor Proteins; Acetates; Achilles Tendon; Acute Kidney Injury; Acute Pain; Acyclic Monoterpenes; Adenine Nucleotides; Adhesins, Escherichia coli; Adipocytes; Adipocytes, Brown; Adipogenesis; Administration, Inhalation; Administration, Oral; Adrenal Cortex Hormones; Adsorption; Adult; Aeromonas hydrophila; Africa; Aged; Aged, 80 and over; Agrobacterium tumefaciens; Air; Air Pollutants; Air Pollution; Air Pollution, Indoor; Algorithms; Alkaloids; Alkynes; Allosteric Regulation; Amines; Amino Acid Sequence; Amino Acids; Amino Acids, Branched-Chain; Aminoisobutyric Acids; Aminopyridines; Amyotrophic Lateral Sclerosis; Anaerobic Threshold; Angiography; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animal Distribution; Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Ankle Joint; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Inflammatory Agents; Antibodies, Bacterial; Antifungal Agents; Antimalarials; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Antiretroviral Therapy, Highly Active; Antiviral Agents; Aotidae; Apelin; Apoptosis; Arabidopsis Proteins; Argentina; Arginine; Artemisinins; Arthritis, Experimental; Arthritis, Rheumatoid; Arthroscopy; Aspergillus; Aspergillus niger; Asteraceae; Asthma; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Auditory Cortex; Autoantibodies; Autophagy; Bacteria; Bacterial Infections; Bacterial Proteins; Bacterial Typing Techniques; Base Composition; Base Sequence; Basketball; Beclin-1; Benzhydryl Compounds; Benzimidazoles; Benzo(a)pyrene; Benzofurans; Benzoxazines; Bereavement; beta Catenin; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Betacoronavirus; Betaine; Binding Sites; Biofilms; Biological Assay; Biological Availability; Biological Evolution; Biomarkers; Biomechanical Phenomena; Biopolymers; Biopsy; Bismuth; Blood Glucose; Blood Platelets; Blood Pressure; Body Composition; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Regeneration; Boron; Botrytis; Brain Ischemia; Brain Neoplasms; Brain-Derived Neurotrophic Factor; Brazil; Breast Neoplasms; Breath Tests; Bronchoalveolar Lavage Fluid; Burkholderia; C-Reactive Protein; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Calcification, Physiologic; Calcium; Calcium Signaling; Calorimetry, Differential Scanning; Cameroon; Camptothecin; Candida; Candida albicans; Capillaries; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Carbohydrate Conformation; Carbon; Carbon Dioxide; Carbon Isotopes; Carcinoma, Ovarian Epithelial; Cardiac Output; Cardiomyopathy, Hypertrophic; Cardiotonic Agents; Cardiovascular Diseases; Caregivers; Carps; Case-Control Studies; Catalase; Catalysis; Cats; CD4 Lymphocyte Count; Cell Culture Techniques; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cellulose; Centrosome; Ceratopogonidae; Chickens; Child; China; Cholera Toxin; Choline; Cholinesterases; Chromatography, High Pressure Liquid; Chromatography, Liquid; Chromatography, Micellar Electrokinetic Capillary; Chromatography, Reverse-Phase; Chronic Disease; Cinnamates; Cities; Citrates; Climate Change; Clinical Trials, Phase III as Topic; Coal; Coal Mining; Cohort Studies; Coinfection; Colchicine; Colony Count, Microbial; Colorectal Neoplasms; Coloring Agents; Common Cold; Complement Factor H; Computational Biology; Computer Simulation; Continuous Positive Airway Pressure; Contrast Media; Coordination Complexes; Coronary Artery Bypass; Coronavirus 3C Proteases; Coronavirus Infections; Coronavirus Protease Inhibitors; Corynebacterium glutamicum; Cosmetics; COVID-19; Creatinine; Cross-Sectional Studies; Crotonates; Crystallography, X-Ray; Cues; Culicidae; Culture Media; Curcuma; Cyclopentanes; Cyclopropanes; Cymbopogon; Cystine; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C19 Inhibitors; 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Based on the hypothesis that high-meat diets may increase breast cancer risk through hormonal pathways, the present analysis compared oestrogens in serum and urine by meat-eating status.. Intervention with repeated measures.. Two randomized soya trials (BEAN1 and BEAN2) among premenopausal healthy women.. BEAN1 participants completed seven unannounced 24 h dietary recalls and donated five blood and urine samples over 2 years. BEAN2 women provided seven recalls and three samples over 13 months. Serum samples were analysed for oestrone (E₁) and oestradiol (E₂) using RIA. Nine oestrogen metabolites were measured in urine by LC-MS. Semi-vegetarians included women who reported consuming <30 g of red meat, poultry and fish daily, and pescatarians those who reported consuming <20 g of meat/poultry but >10 g of fish daily. All other women were classified as non-vegetarians. We applied mixed models to compute least-square means by vegetarian status adjusted for potential confounders.. The mean age of the 272 participants was 41·9 (SD 4·5) years. Serum E₁ (85 v. 100 pg/ml, P = 0·04) and E₂ (140 v. 154 pg/ml, P = 0·04) levels were lower in the thirty-seven semi-vegetarians than in the 235 non-vegetarians. The sum of the nine urinary oestrogen metabolites (183 v. 200 pmol/mg creatinine, P = 0·27) and the proportions of individual oestrogens and pathways did not differ by meat-eating status. Restricting the models to the samples collected during the luteal phase strengthened the associations.. Given the limitations of the study, the lower levels of serum oestrogens in semi-vegetarians than non-vegetarians need confirmation in larger populations.

Topics: Adult; Breast Neoplasms; Cross-Over Studies; Estradiol; Estrogens; Estrone; Female; Hawaii; Humans; Luteal Phase; Meat; Middle Aged; Phytoestrogens; Premenopause; Risk Factors; Soy Foods

Standard estrogenic prodrugs such as estradiol valerate (E2V) and increasingly popular phytoestrogen formulations are commonly prescribed to improve menopausal health. These drugs are metabolized to numerous bioactive compounds, known or unknown, which may exert combinatorial estrogenic effects in vivo. The aim of this study is to develop and validate estrogen receptor (ER) alpha/ERbeta reporter gene and MCF-7 breast cancer cell proliferation bioassays to quantify serum estrogenic activities in a clinical trial setting. We measured changes in serum estrogenicity following ingestion of E2V and compared this to mass spectrometric measurements of its bioactive metabolites, estrone and 17beta-stradiol. ERalpha bioactivity of the 192 serum samples correlated well (R = 79%) with 17beta-estradiol levels, and adding estrone improved R to 0.83 (likelihood ratio test, P < 0.0001), suggesting that the ERalpha assay reflects summated activity of compounds in serum. ERbeta correlated moderately (R = 0.52) with estrone and 17beta-estradiol, with an estrone/17beta-estradiol coefficient ratio that was twice that of ERalpha, indicating estrone was more active on a molar basis in the ERbeta assay. Unlike the ERalpha and ERbeta bioassays, MCF-7 cell proliferation was driven by 17beta-estradiol, and addition of estrone did not increase the predictive value of the model, suggesting that the driver or drivers for breast cancer cell proliferation were not the same as for ERalpha and ERbeta transactivation. In contrast, a decoction of the traditional Chinese medicinal herb Epimedium pubescens did not induce significant changes in estrogenic bioactivity over baseline. These data indicate that ERalpha/ERbeta reporter gene and MCF-7 breast cancer cell proliferation bioassays reflect different aspects of estrogenic activity and that these assays suggest that the Epimedium formulation tested is unlikely to exert significant estrogenic effects in humans.

Topics: Adult; Aged; Androgens; Biological Assay; Breast Neoplasms; Calibration; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Epimedium; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Humans; Middle Aged; Phytoestrogens; Plant Extracts; Steroids; Tandem Mass Spectrometry; Young Adult

Genistein aglycone improves bone metabolism in women. However, questions about the long-term safety of genistein on breast as well as its continued efficacy still remain.. We assessed the continued safety profile of genistein aglycone on breast and endometrium and its effects on bone after 3 yr of therapy.. The parent study was a randomized, double-blind, placebo-controlled trial involving 389 osteopenic, postmenopausal women for 24-months. Subsequently, a subcohort (138 patients) continued therapy for an additional year.. Participants received 54 mg of genistein aglycone daily (n = 71) or placebo (n = 67). Both treatment arms received calcium and vitamin D(3) in therapeutic doses.. Mammographic density was assessed at baseline, 24 and 36 months by visual classification scale and digitized quantification. BRCA1 and BRCA2, sister chromatid exchange, and endometrial thickness were also evaluated. Lumbar spine and femoral neck bone mineral density were also assessed. Secondary outcomes were biochemical levels of bone markers.. After 36 months, genistein did not significantly change mammographic breast density or endometrial thickness, BRCA1 and BRCA2 expression was preserved, whereas sister chromatid exchange was reduced compared with placebo. Bone mineral density increases were greater with genistein for both femoral neck and lumbar spine compared to placebo. Genistein also significantly reduced pyridinoline, as well as serum carboxy-terminal cross-linking telopeptide and soluble receptor activator of NF-kappaB ligand while increasing bone-specific alkaline phosphatase, IGF-I, and osteoprotegerin levels. There were no differences in discomfort or adverse events between groups.. After 3 yr of treatment, genistein exhibited a promising safety profile with positive effects on bone formation in a cohort of osteopenic, postmenopausal women.

Topics: Aged; Biomarkers; Bone Density; Bone Diseases, Metabolic; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Double-Blind Method; Endometrium; Female; Genistein; Humans; Mammography; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; RNA, Messenger; Sister Chromatid Exchange

To assess the safety and tolerability of a standardized 40 mg red clover isoflavone dietary supplement (Promensil, Novogen) in women with a family history of breast cancer to evaluate the feasibility of using the supplement for prevention of breast cancer in healthy women.. Healthy women aged 35-70 years (n = 401) with at least one first-degree relative with breast cancer received red clover isoflavones or placebo for three years in a randomized, double-blind, placebo-controlled pilot trial. Participants were assessed clinically and blood samples taken for biochemical analysis every six months. In addition, study participants underwent mammography, bone density and transvaginal ultrasound (postmenopausal women only) once per year.. No significant differences in breast density, endometrial thickness, serum cholesterol, follicle stimulating hormone levels and bone mineral density were detected between those taking red clover isoflavones and placebo. In postmenopausal women, some significant differences in bone marker levels were seen between active and placebo groups, at six months and at 12 months. The adverse event profile was similar across all red clover isoflavone and placebo groups.. This three-year study supports the growing body of evidence that treatment with red clover isoflavones is safe and well tolerated in healthy women. Supplements containing red clover isoflavones did not adversely affect breast density, skeletal strength or cardiovascular status. In postmenopausal women, endometrial status was not adversely affected. The adverse event profile was similar between red clover isoflavones, and placebo and endocrine status did not differ.

Topics: Aged; Breast Neoplasms; Dietary Supplements; Double-Blind Method; Female; Humans; Isoflavones; Middle Aged; Phytoestrogens; Phytotherapy; Postmenopause; Premenopause; Trifolium

Menopausal symptoms are a major survivorship issue for patients treated for breast cancer. There are increasing concerns over the use of hormone replacement therapy (HRT) in this setting and a growing consumer interest in "natural" therapies. It had been suggested that soy phyto-oestrogens might be beneficial in the treatment of menopausal symptoms. Seventy-two patients with a histologically confirmed pre-existing diagnosis of breast cancer who were having menopausal symptoms were randomised between 12 weeks of treatment with soy capsules or placebo. Quality of life and menopausal symptom scores were assessed at baseline, 4, 8 and 12 weeks. There was no statistical difference in menopausal symptom scores or quality of life between the two arms of the study.

Topics: Adult; Aged; Breast Neoplasms; Capsules; Double-Blind Method; Female; Hot Flashes; Humans; Isoflavones; Menopause; Middle Aged; Nonprescription Drugs; Phytoestrogens; Quality of Life; Soybean Proteins

Observational studies suggest that dietary isoflavones reduce breast cancer risk, and this may be caused in part by effects on endogenous hormone concentrations. Because intestinal bacteria metabolize isoflavones, it was hypothesized that consumption of probiotic bacteria would enhance the biologic effects of isoflavones, including effects on endogenous hormones.. Twenty (20) postmenopausal breast cancer survivors and 20 healthy postmenopausal women completed four 42-day diet periods in a randomized, crossover design. They received one of the following: isolated soy protein; isolated milk protein; soy + probiotic capsules; or milk + probiotic capsules. Each protein supplement provided 0.38 g protein/(kg body weight/day) (26.6 +/- 4.5 g protein/day) and soy protein provided 0.64 mg isoflavones/(kg body weight/day) (44.4 +/- 7.5 mg isoflavones/day). Probiotic capsules provided 10(9) colony-forming units Lactobacillus acidophilus (strain DDS-1), Bifidobacterium longum, and 15-20 mg fructo-oligosaccharide.. Plasma samples were collected at baseline and after each diet for analysis of estrogens, follicle-stimulating hormone (FSH), androgens, and sex hormone?binding globulin (SHBG).. Hormone levels were not affected by soy, probiotic supplements, or equol producer status, and neither cancer status nor equol producer status altered the effects of soy or probiotics. Furthermore probiotics did not alter the effects of soy consumption. Soy protein tended to decrease SHBG compared to milk protein diets (p = 0.05), although both proteins significantly decreased SHBG relative to baseline (p = 0.0001 and p = 0.03).. These data suggest that short-term, moderate consumption of isoflavone-containing soy protein and consumption of these particular probiotic capsules do not significantly alter reproductive hormone concentrations in breast cancer survivors or controls, regardless of equol producer status.

Topics: Administration, Oral; Analysis of Variance; Breast Neoplasms; Cross-Over Studies; Female; Gonadal Hormones; Humans; Isoflavones; Middle Aged; Milk Proteins; Phytoestrogens; Postmenopause; Probiotics; Soybean Proteins

High phytoestrogen intake among Asian women has been thought to explain the low risk of bone fractures in these populations. In a randomized placebo-controlled trial we studied the effects of isoflavonoids on urinary output of the N-terminal cross-linked telopeptide of type I collagen, pyridinoline (Pyr), and deoxypyridinoline (Dpyr) (bone resorption markers) and serum levels of bone-specific alkaline phosphatase and N-terminal and C-terminal procollagen type I (bone formation markers). Fifty-five postmenopausal women with a history of breast cancer used phytoestrogens (114 mg of isoflavonoids) or placebo tablets daily for 3 months; the treatment regimens were then crossed over after a 2-month washout period. The markers were measured before and on the last day of each treatment period. Bone resorption was reduced during phytoestrogen use, as reflected in falls in the urinary output of Pyr (9%; P = 0.001) and Dpyr (5%; P = 0.008). Compared with the placebo group, the fall in Dpyr was significant (P = 0.022) and the falls in Pyr (P = 0.084) and N-terminal cross-linked telopeptide of type I collagen (P = 0.082) showed a trend toward significance. Bone formation markers were not affected by this regimen. Thus, isoflavonoid-induced inhibition of bone resorption may contribute to the low risk of osteoporosis in Asian women.

Topics: Adult; Aged; Bone Remodeling; Breast Neoplasms; Cross-Over Studies; Female; Hot Flashes; Humans; Isoflavones; Middle Aged; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Postmenopause; Risk Factors

To confirm the results of an earlier study showing premenopausal equol excretors to have hormone profiles associated with reduced breast cancer risk, and to investigate whether equol excretion status and plasma hormone concentrations can be influenced by consumption of probiotics.. A randomized, single-blinded, placebo-controlled, parallel-arm trial.. In all, 34 of the initially enrolled 37 subjects completed all requirements.. All subjects were followed for two full menstrual cycles and the first seven days of a third cycle. During menstrual cycle 1, plasma concentrations of estradiol (E(2)), estrone (E(1)), estrone-sulfate (E(1)-S), testosterone (T), androstenedione (A), dehydroepiandrosterone-sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) were measured on cycle day 2, 3, or 4, and urinary equol measured on day 7 after a 4-day soy challenge. Subjects then received either probiotic capsules (containing Lactobacillus acidophilus and Bifidobacterium longum) or placebo capsules through day 7 of menstrual cycle 3, at which time both the plasma hormone concentrations and the post-soy challenge urinary equol measurements were repeated.. During menstrual cycle 1, equol excretors and non-excretors were not significantly different with respect to subject characteristics, diet, or hormone concentrations. Significant inverse correlations were found between E(2) and body mass index (BMI) (P=0.02), SHBG and BMI (P=0.01), DHEA-S and dietary fiber (P=0.04), and A and protein:carbohydrate ratio (P=0.02). Probiotic consumption failed to significantly alter equol excretor status or hormone concentrations during menstrual cycle 3, although there were trends towards decreased concentrations of T (P=0.14) and SHBG (P=0.10) in the probiotic group.. We were unable to verify a previously reported finding of premenopausal equol excretors having plasma hormone concentrations different from those of nonexcretors. Furthermore, a 2-month intervention with probiotic capsules did not significantly alter equol excretion or plasma hormone concentrations.

Topics: Adult; Bifidobacterium; Body Mass Index; Breast Neoplasms; Dehydroepiandrosterone Sulfate; Dietary Fiber; Equol; Estradiol; Female; Hormones; Humans; Isoflavones; Lactobacillus acidophilus; Menstrual Cycle; Phytoestrogens; Premenopause; Probiotics; Risk Factors

Soy phytoestrogens were suggested to reduce the risk of a number of diseases including breast cancer. Given that these compounds are metabolized by bacteria, alteration of intestinal bacteria and enzymes may affect phytoestrogen metabolism. We hypothesized that probiotics, when consumed with soy protein, would increase plasma isoflavones, as well as equol producer frequency, in postmenopausal women. We further hypothesized that these effects would differ between women who have had breast cancer and women who have not. To test these hypotheses, 20 breast cancer survivors and 20 controls completed four 6-wk treatments in a randomized, crossover design: supplementation with soy protein (S) (26.6 +/- 4.5 g protein, 44.4 +/- 7.5 mg isoflavones/d); soy + probiotics (S+P) (10(9) colony-forming units Lactobacillus acidophilus DDS+1 and Bifidobacterium longum, 15-30 mg fructooligosaccharide/d); milk protein (M) (26.6 +/- 4.5 g protein/d); and milk + probiotics (M+P). Plasma phytoestrogen concentrations did not differ between controls and survivors, although genistein tended to be lower in survivors at baseline (P = 0.15), and during soy (P = 0.16) and milk protein (P = 0.16) consumption. As expected, soy consumption increased plasma phytoestrogen concentrations (P < 0.0001). Plasma phytoestrogen concentrations and the number of equol producers did not differ between the S and S+P diets. At the same time, plasma equol concentrations as well as urinary equol excretion in 2 subjects were more than 7-fold different between the 2 diets. These results indicate that this particular probiotic supplement does not generally affect plasma isoflavones, although the large differences between plasma and urinary equol in some subjects suggest that equol producer status may be modifiable in some individuals.

Topics: Biological Availability; Breast Neoplasms; Cross-Over Studies; Dietary Proteins; Female; Humans; Isoflavones; Middle Aged; Milk Proteins; Phytoestrogens; Plant Preparations; Postmenopause; Probiotics; Soybean Proteins

Phytoestrogens are popular in treatment of menopause, although scientific evidence is insufficient as to their efficacy. We studied the effects of daily use of isoflavonoids on climacteric symptoms and quality of life in patients with a history of breast cancer.. Sixty-two postmenopausal symptomatic women were randomized to use either phytoestrogen (tablets containing 114 mg of isoflavonoids) or a placebo for 3 months; the treatment regimens were reversed after a 2-month washout period. Fifty-six women completed the study. Menopausal symptoms were recorded on the Kupperman index and the visual analogue scale, and working capacity and mood changes were assessed via validated questionnaires. In addition, we followed the levels of phytoestrogens, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and sex hormone-binding globulin. Liver enzymes and creatinine were also assessed at each visit.. The phytoestrogen regimen raised the circulating levels of phytoestrogens (daidzein, genistein, equol) 19- to 106-fold. The Kupperman index was reduced by 4.2 +/- 9.6 (mean +/- standard deviation) (15.5%) during phytoestrogen use and similarly by 4.0 +/- 8.1 (14.7%) during placebo use (P nonsignificant). The quality of life parameters (working capacity, mood changes) were unaffected by phytoestrogen. In addition, the phytoestrogen regimen caused no changes in FSH, LH, estradiol, or sex hormone-binding globulin. Phytoestrogen treatment was well tolerated and caused no changes in liver enzymes, creatinine, body mass index, or blood pressure. Of the 56 women, 25 (44.6%) preferred the phytoestrogen regimen, 15 preferred the placebo (26.8%), and 16 (28.6%) reported no preference (nonsignificant).. Pure isoflavonoids did not alleviate subjective menopausal symptoms in breast cancer patients.

Topics: Breast Neoplasms; Cross-Over Studies; Double-Blind Method; Estradiol; Estrogens, Non-Steroidal; Female; Follicle Stimulating Hormone; Humans; Isoflavones; Luteinizing Hormone; Phytoestrogens; Plant Preparations; Postmenopause; Quality of Life; Sex Hormone-Binding Globulin

Steroid sex hormones play a central role in breast carcinogenesis. Evidence from in vitro and animal studies suggests that phytoestrogens may inhibit the development of mammary tumors through their role in regulating the synthesis, metabolism, and signal transduction of steroid hormones. In a study of 117 case-control pairs of postmenopausal women in Shanghai, we investigated whether the association between urinary phytoestrogen excretion and breast cancer risk may differ by levels of endogenous steroid sex hormones, sex hormone binding globulin (SHBG), body mass index (BMI), and waist:hip ratio (WHR). Fasting morning blood and urine samples were collected for the analysis of urinary isoflavonoids and mammalian lignans, as well as blood levels of SHBG and selected steroid hormones. For cancer patients, samples were collected before any cancer therapy. Conditional logistic regression models were used to estimate odds ratios and 95% confidence intervals after adjusting for potential confounding factors. The inverse associations between urinary phytoestrogens and breast cancer risk were found to be more evident among women with a high BMI or WHR than those with a low level of these anthropometric measurements. Although a reduced risk of breast cancer was observed among women with a high excretion rate of urinary isoflavonoids in all of the strata defined by blood SHBG and steroid hormones, the inverse association was more pronounced among women with a high blood concentration of estradiol, a low level of estrone sulfate, or a low level of SHBG. The risks of breast cancer were also reduced with increasing excretion rate of mammalian lignans, although no test for a linear association was statistically significant in stratified analyses. Findings from this study suggest that the potential protective association of phytoestrogens may be modified by BMI, WHR, and blood levels of SHBG, and steroid hormones.

Topics: Adult; Age Factors; Anthropometry; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Case-Control Studies; China; Dehydroepiandrosterone Sulfate; Eating; Estrogens; Female; Fibroadenoma; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Plant Preparations; Risk Factors; Sex Hormone-Binding Globulin; Statistics as Topic; Testosterone; Women's Health

Phytoestrogens are thought to be beneficial to vascular health. Possible mechanisms of action could involve C-reactive protein (CRP), endothelial E-selectin, and nitric oxide. We therefore designed a randomized, placebo-controlled, double-blind trial in which we studied the effects of isoflavonoids on CRP, E-selectin, and nitrate-nitrite (NO(x); reflecting the release of nitric oxide) in postmenopausal women. Fifty-six postmenopausal women (FSH > 30 U/liter) with a history of breast cancer used (in a randomized order) phytoestrogen (114 mg isoflavonoids) or placebo tablets daily for 3 months; the treatment regimens were crossed over after a 2-month washout period. The serum levels of CRP and E-selectin, and plasma levels of NO(x) were measured before and on the last day of each treatment. The phytoestrogen regimen did not affect the levels of either CRP (P = 0.584) or NO(x) (P = 0.270), but the levels of E-selectin were reduced by 4.0% (2.9 ng/ml; P = 0.031) during phytoestrogen use and by 2.2% (1.3 ng/ml; P = 0.023) during placebo use. No difference was found at any marker at 3 months between the groups. In conclusion, our data, suggesting neutral effects of phytoestrogens on CRP, E-selectin, and nitric oxide, fail to support a vasoprotective role of phytoestrogens.

Topics: Adult; Aged; Breast Neoplasms; C-Reactive Protein; Cross-Over Studies; E-Selectin; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Middle Aged; Nitrates; Phytoestrogens; Phytotherapy; Plant Preparations

Fourteen premenopausal women participated in a randomized, crossover controlled feeding study of three diets, each two menstrual cycles long. We compared a high saturated fat Western diet (control diet) with two other diets: the control diet plus soy protein (soy diet) and the control diet with polyunsaturated fat (PUFA diet) replacing most of the saturated fat. We measured reproductive and serum hormones, urinary estrogen metabolites and isoflavonoids, and menstrual cycle length. In the follicular phase, prolactin concentrations significantly decreased by 3.6 micrograms/dl (P = 0.047), follicle-stimulating hormone concentrations slightly increased by 0.1 IU/l (P = 0.076), and cortisol concentrations slightly decreased by 81.8 nmol/l (P = 0.088) with the PUFA diet vs. the control diet. The soy diet slightly increased menstrual cycle length by 1.8 +/- 0.7 days (P = 0.088) and significantly increased (P < 0.0001) urinary isoflavonoid excretion. These well-controlled diets did not affect serum estrogens or urinary estrogen metabolites, suggesting that type of fat or consumption of soy with a high saturated fat diet may not alter breast cancer risk by these mechanisms.

Topics: Adult; Biomarkers; Breast Neoplasms; Cross-Over Studies; Dietary Fats; Estrogens, Non-Steroidal; Fatty Acids, Unsaturated; Female; Hormones; Humans; Isoflavones; Luteal Phase; Phytoestrogens; Plant Preparations; Premenopause; Reference Values; Risk Factors; Single-Blind Method; Soybean Proteins

Topics: Adult; Breast Neoplasms; Chromatography, High Pressure Liquid; Dietary Supplements; Double-Blind Method; Estrogens; Estrogens, Non-Steroidal; Female; Hormones; Humans; Isoflavones; Middle Aged; Phytoestrogens; Plant Preparations; Premenopause; Risk Factors

Vasomotor symptoms, such as hot flashes and night sweats, in breast cancer survivors are often worsened by chemotherapy and tamoxifen, and/or the discontinuation of hormone replacement therapy at diagnosis. This study evaluated the acceptability and effectiveness of a soy beverage containing phytoestrogens as a treatment for hot flashes in postmenopausal women with breast cancer.. A randomized, placebo-controlled, double-blind clinical trial was conducted in postmenopausal women with moderate hot flashes who were previously treated for early-stage breast cancer. Women were stratified for tamoxifen use and randomized to a soy beverage (n = 59) containing 90 mg of isoflavones or to a placebo rice beverage (n = 64). Women recorded the number and severity of hot flashes daily with a daily menopause diary for 4 weeks at baseline and for 12 weeks while consuming 500 mL of a soy or placebo beverage.. There were no significant differences between the soy and placebo groups in the number of hot flashes or hot flash scores. However, presumably because of a strong placebo effect, both groups had significant reductions in hot flashes. Mild gastrointestinal side effects were experienced by both groups but occurred with greater frequency and severity with soy. The mean serum genistein concentration at 6 weeks was significantly higher in women who consumed soy (0.61 +/- 0.43 micromol/L) compared with placebo (0.43 +/- 0.37 micromol/L) (P =.02). Overall acceptability and compliance were high and similar in both groups.. The soy beverage did not alleviate hot flashes in women with breast cancer any more than did a placebo. Future research into other compounds is recommended to identify safe and effective therapies for hot flashes in breast cancer survivors.

Topics: Breast Neoplasms; Double-Blind Method; Estrogens, Non-Steroidal; Female; Glycine max; Hot Flashes; Humans; Isoflavones; Middle Aged; Phytoestrogens; Plant Preparations; Postmenopause; Treatment Outcome

Hot flashes represent a significant clinical problem for some breast cancer survivors. Safe, effective treatment is needed for this prominent clinical problem. Although it has been shown that estrogen or progesterone replacement therapy can alleviate this problem, there are continued safety concerns regarding the use of hormonal therapies in these women. Based on anecdotal information, we hypothesized that soy-derived phytoestrogens, weak estrogen-like substances in the soybean that demonstrate estrogen agonist and/or antagonist effects when they bind to estrogen receptors, could alleviate hot flashes. This current trial was designed to investigate this hypothesis.. This double-blind clinical trial involved breast cancer survivors with substantial hot flashes. After randomization, patients underwent a 1-week baseline period with no therapy. This was followed by 4 weeks of either soy tablets or placebo. The patients then crossed over to the opposite arm in a double-blind manner for the last 4 weeks. Patients completed a daily questionnaire documenting hot flash frequency, intensity, and perceived side effects.. Of the 177 women who were randomized and started the study substance, 155 (88%) provided useable data over the first 5 weeks; 149 provided usable data over the entire 9 weeks. There was no suggestion that the soy product was more effective in reducing hot flashes than the placebo. At study completion, patients preferred the soy product 33% of the time, the placebo 37% of the time, and neither substance 31% of the time. No toxicity was observed.. The soy product did not alleviate hot flashes in breast cancer survivors.

Topics: Adolescent; Adult; Breast Neoplasms; Double-Blind Method; Estrogens, Non-Steroidal; Female; Glycine max; Hot Flashes; Humans; Isoflavones; Middle Aged; Phytoestrogens; Plant Preparations; Treatment Outcome

Isoflavones are soy phytoestrogens that have been suggested to be anticarcinogenic. Our previous study in premenopausal women suggested that the mechanisms by which isoflavones exert cancer-preventive effects may involve modulation of estrogen metabolism away from production of potentially carcinogenic metabolites [16alpha-(OH) estrone, 4-(OH) estrone, and 4-(OH) estradiol] (X. Xu et al., Cancer Epidemiol. Biomark. Prev., 7: 1101-1108, 1998). To further evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 18 healthy postmenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for 93 days, during which subjects consumed their habitual diets supplemented with soy protein isolate providing 0.1 (control), 1, or 2 mg isoflavones/kg body weight/day (7.1 +/- 1.1, 65 +/- 11, or 132 +/- 22 mg/day). A 72-h urine sample was collected 3 days before the study (baseline) and days 91-93 of each diet period. Urine samples were analyzed for 10 phytoestrogens and 15 endogenous estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Compared with the soy-free baseline and very low isoflavone control diet, consumption of 65 mg isoflavones increased the urinary 2/16alpha-(OH) estrone ratio, and consumption of 65 or 132 mg isoflavones decreased excretion of 4-(OH) estrone. When compared with baseline values, consumption of all three soy diets increased the ratio of 2/4-(OH) estrogens and decreased the ratio of genotoxic: total estrogens. These data suggest that both isoflavones and other soy constituents may exert cancer-preventive effects in postmenopausal women by altering estrogen metabolism away from genotoxic metabolites toward inactive metabolites.

Topics: Analysis of Variance; Anticarcinogenic Agents; Breast Neoplasms; Cross-Over Studies; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Least-Squares Analysis; Middle Aged; Phytoestrogens; Plant Preparations; Postmenopause; Soybean Proteins

Prevalent as a major phenolic ingredient of soy and soy products, genistein is recognized as an eminent phytoestrogen owing to its interacting ability with estrogen receptors (ERs). The metabolic conversion of plant-derived genistin to genistein by gut microbes and intestinal enzymes enhances its absorption at intestinal pH of ~7.5-7.8. Genistein interferes in breast cancer (BC) development via pleiotropic actions on cell proliferation, survival, angiogenesis, and apoptosis. Though multiple investigations have demonstrated genistein intake-driven reduced BC risk, similar efficacy has not been replicated in clinical trials. Furthermore, multiple studies have structurally and functionally equated genistein extents with 17-β-estradiol (E2), the most available physiological estrogen in females, culminating in aggravated BC growth. Of note, both genistein and E2 function via interacting with ERs (ERα and ERβ). However, although E2 shows almost equal affinity towards both ERα and ERβ, genistein shows more affinity towards ERβ than ERα. Our cautious literature survey revealed typical intake mode, ER expression pattern and the ratio of ERα and ERβ, transactivators/ regulators of ERα and ERβ expression and activities, patient age, and menopausal status as decisive factors affecting genistein BC activities. Of further interest are the mechanisms by which genistein inhibits triple-negative breast cancers (TNBCs), which lack ERs, progesterone receptors (PRs), and human epidermal growth factor receptors (HER2). Herein, we attempt to understand the dosage-specific genistein actions in BC cells and patients with an insight into its better response via derivative development, nanocarrier-assisted, and combinatorial delivery with chemotherapeutic drugs.

Topics: Biological Availability; Breast Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genistein; Humans; Phytoestrogens; Receptors, Estrogen

The main task of targeted therapy is the selective destruction of cancer cells without affecting normal ones. For these purposes, small molecules and antibodies are used that target specific receptors and proteins or block signaling pathways in tumor cells. The natural phytoestrogens daidzein (Dz) and genistein (Gn) possess binding capacity to estrogen receptors (ER). Methionine γ-lyase (MGL) is promising in two strategies of antitumor therapy: for the elimination of l-methionine, which is necessary for the proliferation of tumor cells, and for the production of cytotoxic dialkyl thiosulfinates in situ. For delivery of MGL-loaded nanocapsules (nanoreactors) to the surface of cancer cells a technique for Dz or Gn incorporation into the shell of polyionic vesicles (PICsomes) was developed. The nanoreactors were characterized by dynamic light scattering and transmission electron microscopy. The enzyme retained its catalytic efficiency inside the decorated PICsomes. The binding of Dz/Gn-nanoreactors to the surface of ER + MCF7 breast adenocarcinoma cells was demonstrated. For the first time an influence of enzyme-loaded PICsomes and their individual components on embryos development was evaluated. The high rate of blastocysts formation (>80%) was observed for all tested components and nanoreactors themselves. A strong inhibitory effect on the early embryonic development of MGL-loaded PICsomes in the presence of S-alkyl-l-cysteine sulfoxide substrates was showed. This proves that the substrates can freely penetrate through the polymer shell of the polyionic vesicle and are cleaved by MGL to form cytotoxic thiosulfinates. The data obtained for phytoestrogens decorated PICsomes may be applied in enzyme therapy of malignant tumors.

Topics: Antineoplastic Agents; Breast Neoplasms; Female; Humans; Methionine; Nanocapsules; Phytoestrogens; Receptors, Estrogen

The propensity of breast cancer to preferentially metastasize to the skeleton is well known. Once established in bone metastatic breast cancers have a poor prognosis due to their ability to promote extensive bone loss which augments tumor burden. Unfortunately, current anti-resorptive therapies for skeletal metastasis are typically prescribed after secondary tumors have formed and are palliative in nature. One group of compounds with the potential to reduce both tumor burden and osteolysis are phytoestrogens (PE), but the mechanisms mediating a beneficial effect are unclear. Therefore, the current study examined the effect of genistein and coumestrol alone or in combination on breast cancer cell number, expression of mediators of preferential skeletal metastasis, bone matrix attachment and tumor-induced osteoclast formation. Results showed that genistein and coumestrol significantly reduced viable cell number in an estrogen receptor dependent manner (p < 0.05), whereas combinations of PE had no effect. In addition, genistein and coumestrol significantly reduced expression of genes driving epithelial to mesenchymal transition (snail), bone attachment (CXCR4 and integrin αV) and osteolysis (PTHrP and TNF-α). In keeping with this genistein and coumestrol significantly suppressed attachment of breast cancer cells to bone matrix and inhibited tumor and RANKL-induced osteoclast formation. Our data suggests that phytoestrogens not only decrease breast cancer cell viability but also antagonize essential tumor bone interactions that establish and drive the progression of skeletal metastasis.

Topics: Bone Matrix; Bone Neoplasms; Breast Neoplasms; Cell Survival; Coumestrol; Epithelial-Mesenchymal Transition; Female; Genistein; Humans; MCF-7 Cells; Osteogenesis; Osteolysis; Phytoestrogens

Rutin has been reported as a potential anti-cancer agent for several decades. This study evaluated the effects of rutin on the proliferation, metastasis, and angiogenesis of MDA-MB-231 and MCF-7 breast cancer cell lines. Increasing concentrations of rutin significantly stimulated the proliferation of MDA-MB-231 and MCF-7 cells compared to controls. Wound scratch assay demonstrated that rutin had an inducing effect on the migration of the cells. In MDA-MB-231 and MCF-7 cells, rutin upregulated MKI67, VIM, CDH2, FN1, and VEGFA and downregulated CDH1 and THBS1 genes. It also increased N-cadherin and VEGFA and decreased E-cadherin and thrombospondin 1 protein expression. Our data indicated that rutin could stimulate proliferation, migration, and pro-angiogenic activity in two different breast cancer cell lines. This phytoestrogen induced invasion and migration of both cell lines by a mechanism involving the EMT process. This suggests that rutin may act as a breast-cancer-promoting phytoestrogen.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Humans; MCF-7 Cells; Phytoestrogens

Phytoestrogens are plant-derived compounds that are structurally similar to endogenous estrogens. Studies have shown phytoestrogens to have possible health benefits although they could also act as endocrine disruptors. This is particularly relevant for estrogen-dependent cancers since estrogens increase risk of breast, endometrial, and ovarian cancer. Using data from the National Health and Nutritional Examination Survey (NHANES), we assessed the associations between urinary phytoestrogens (daidzein, equol, o-Desmethylangolensin (O-DMA), genistein, enterodiol, enterolactone) and breast, endometrial, and ovarian cancer using multivariate logistic regression with odds ratios (ORs) and 95% confidence intervals (CIs). Cancer diagnosis and other characteristics were collected via in-person questionnaires. We found women in the highest tertile for daidzein and enterodiol had over twice the odds of having breast cancer (OR = 2.51, 95% CI 1.44-4.36 for daidzein, OR = 2.78, 95% CI 1.44-5.37 for enterodiol). In addition, women in the highest tertiles for daidzein and genistein had three to four times the odds of having endometrial cancer, respectively (OR = 3.09, 95% CI 1.01-9.49 for daidzein, OR = 4.00, 95% CI 1.38-11.59 for genistein). Overall, phytoestrogens were positively associated with breast and endometrial cancer although the associations varied by phytoestrogen type. Additional studies are needed to further inform phytoestrogens' role in disease etiology.Supplemental data for this article is available online at at https://doi.org/10.1080/01635581.2021.2020304.

Topics: Breast Neoplasms; Endometrial Neoplasms; Estrogens; Female; Genistein; Humans; Isoflavones; Lignans; Nutrition Surveys; Ovarian Neoplasms; Phytoestrogens

High phytoestrogen intake during adolescence is associated with a reduced risk of breast cancer. Breast density (BD) is a strong predictor of breast cancer and can be considered an early marker. We aim to assess the association between the mean habitual intake of isoflavones, lignans, and total phytoestrogens intake during puberty until 2 years after menarche onset and absolute fibroglandular volume (AFGV) and percentage of fibroglandular volume (%FGV) in Hispanic girls at the end of puberty.. Longitudinal study set up in the Growth and Obesity Chilean Cohort Study (GOCS). We included 329 girls with dietary data (multiple 24-hours recalls) from puberty until 2 years after menarche onset (81% had 2-4 recalls). Two international datasets were used to estimate isoflavones, lignans, and total phytoestrogens in the diet. Breast composition was measured by dual energy X-ray absorptiometry at 2 years after menarche. Multiple linear regression models were used to assess the association between isoflavones, lignans, and total phytoestrogens intake and AFGV and %FGV.. The average total phytoestrogen intake was 1 mg/day and %FGV was 50.7% (SD = 15.2) and AFGV 218.8 cm3 (SD = 79.3). An inverse association was found between consumption of isoflavones and AFGV, as well as, with total phytoestrogens [Q4 vs. Q1 adjusted model ß = -49.2 cm3; 95% CI (-85.5 to -13.0)].. Girls with a higher intake of total phytoestrogens and isoflavones during puberty until 2 years after menarche onset had significantly lower AFGV.. Although the intake of phytoestrogens is low in Western populations, higher consumption of them during a critical period of life like puberty could be beneficial to reduce breast cancer during adulthood.

Topics: Adolescent; Adult; Breast Density; Breast Neoplasms; Cohort Studies; Diet; Female; Humans; Isoflavones; Lignans; Longitudinal Studies; Menarche; Phytoestrogens

Breast cancer is the most commonly diagnosed cancer worldwide. Previously, we reported that calycosin, a typical isoflavone phytoestrogen, triggers apoptosis and is associated with lncRNA HOTAIR in the estrogen receptor (ER)-positive breast cancer MCF-7-cell line. In the present study, we aim to uncover the mechanism of lncRNA HOTAIR in the inhibitory effect induced by calycosin in both ER-positive and ER-negative breast cancer cell lines. Results show that calycosin significantly inhibits proliferation and triggers apoptosis in both ER-positive (MCF-7 and T47D) and ER-negative (MDA-MB-231 and SK-BR-3) breast cancer cell lines, accompanied by downregulation of lncRNA HOTAIR expression. Accordingly, knockdown of lncRNA HOTAIR promotes the anti-tumor effect of calycosin, while overexpression of lncRNA HOTAIR attenuates this effect. Meanwhile, the expression levels of HuR and IGF2BP1 are also reduced by calycosin. More importantly, calycosin facilitates the downregulation of HuR and IGF2BP1 caused by decreasing lncRNA HOTAIR expression, and the upregulation of HuR and IGF2BP1 caused by overexpression of lncRNA HOTAIR is weakened by calycosin. These results demonstrate that downregulating HuR and IGF2BP1 by suppressing lncRNA HOTAIR results in inhibited growth of breast cancer cells by calycosin. In addition, the binding of HuR and IGF2BP1 to lncRNA HOTAIR is detected by RIP assay, implying an interaction between these two proteins and lncRNA HOTAIR. Together, lncRNA HOTAIR may play a carcinogenic role in breast cancer development and has the potential to be a novel therapeutic target for breast cancer in the future, especially in isoflavone phytoestrogen therapy.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Phytoestrogens; RNA, Long Noncoding

Phytoestrogens have been investigated for their potential anti-tumorigenic effects in various cancers including breast cancer. Emodin being a phytoestrogen shows anti-carcinogenic properties especially in estrogen receptor positive (ER+) breast cancers. The aim of this study is to identify the molecular mechanism and related biological pathways in both (ER+) MCF-7 and (ER-) MDA-MB-231 breast cancer cell lines upon Emodin treatment via microarray analysis in order to find out therapeutic biomarkers. In both cell lines, first differentially expressed genes were identified, then gene ontology and functional pathway enrichment analyses were performed. Genes regulated through multiple pathways were studied together with literature and a gene cluster was determined for each cell line. Further GeneMANIA and STRING databases were used to study the interactions within the related gene clusters. The results showed that, the genes which are related to cell cycle were significantly regulated in both cell lines. Also, Forkhead Box O1-related genes were found to be prominent in MCF-7 cells. In MDA-MB-231 cells, spindle attachment checkpoint mechanism-related genes were regulated, remarkably. As a result, novel gene regulations reported in this study in response to Emodin will give more information about its metabolism and antiproliferative effect, especially in ER + cells.

Topics: Biology; Breast Neoplasms; Cell Line, Tumor; Emodin; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Phytoestrogens

This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Benzoates; Breast Neoplasms; Bridged Bicyclo Compounds; Cycloheptanes; Drug Screening Assays, Antitumor; Female; Ferula; Humans; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Phytoestrogens; Sesquiterpenes

Low risk of breast cancer is observed among females consuming a moderate quantity of soy throughout their life. The present study was conducted to evaluate the anticancer potential of Daidzein, one of the major Isoflavones in soy using Human breast cancer cells MCF-7.. MCF-7 were subjected to various doses of Daidzein treatment to determine the IC50 value. Onset of apoptosis was ascertained by AnnexinV assay and caspase 3/7 activity post treatment. Expression of pro-apoptotic protein Bax and anti-apoptotic protein Bcl2 was also assessed to further confirm apoptotic mode of cell death. ROS production post treatment with Daidzein was assessed to ascertain the apoptosis via intrinsic pathway. Expression of ER α and ER β was evaluated by western blot analysis.. Human breast cancer cells MCF-7 were found to be sensitive to Daidzein treatment, with an IC50 value of 50µM. Increased percentage of treated cells stained with Annexin V confirmed apoptosis mediated cell death. Activity of Caspase 3/7 activity was found to be 1.4-fold higher in Daidzein treated cells than control cells, confirming apoptosis. Daidzein caused over expression of Bax and down-regulated expression of Bcl2. There has been an outburst of ROS in Daidzein treated cells indicating that Daidzein induces apoptosis via intrinsic pathway. A decrease in the expression of ER α and increase in levels of ER β has been observed which are conducive indicator of apoptosis.. In conclusion, the present study suggests that Daidzein induces apoptosis in MCF-7 cells by mitochondrial pathway along with lowering the ratio of ER α/β and an outburst of Reactive Oxygen Species(ROS).

Topics: Adenocarcinoma; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Culture Techniques; Estrogen Receptor alpha; Estrogen Receptor beta; Humans; Inhibitory Concentration 50; Isoflavones; MCF-7 Cells; Phytoestrogens; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Menopause, caused by decreases in estrogen production, results in symptoms such as facial flushing, vaginal atrophy, and osteoporosis. Although hormone replacement therapy is utilized to treat menopausal symptoms, it is associated with a risk of breast cancer development. We aimed to evaluate the estrogenic activities of

Topics: Animals; Breast Neoplasms; Cell Proliferation; Estrogen Receptor alpha; Female; Humans; Ligands; MCF-7 Cells; Molecular Structure; Organ Size; Phytoestrogens; Plant Components, Aerial; Plant Extracts; Plant Roots; Poaceae; Rats, Sprague-Dawley; Structure-Activity Relationship; Uterus

Lignans are associated with improved postmenopausal breast cancer (BC) survival, but whether these associations, particularly with enterolactone (major lignan metabolite), persist over time is unclear. Little is known about other phytoestrogens on prognosis in long-term survivors. The study examines associations of prognosis with 1) circulating postdiagnosis enterolactone, 2) eight circulating phytoestrogen metabolites, and 3) changes in enterolactone and genistein. In a German cohort of 2,105 postmenopausal BC patients with blood samples collected at recruitment 2002-2005 (baseline) and re-interview in 2009 (follow-up), delay-entry Cox proportional hazards regression was used. Landmark analysis showed that circulating enterolactone (log2) associations with 5-year survival changed over time, with strongest hazard ratios of 0.89 (95% CI, 0.80-0.99) at blood draw (BD) and 0.86 (0.77-0.97) at 2 years post-BD for BC mortality, and 0.87 (0.80-0.95) at BD and 0.84 (0.76-0.92) at 3 years post-BD for all-cause mortality, which attenuated thereafter. In long-term survivors, increasing concentrations of genistein (1.17, 1.01-1.36), resveratrol (1.19, 1.02-1.40), and luteolin (1.96, 1.07-3.58) measured in follow-up blood samples were associated with poorer subsequent prognosis. Neither enterolactone at follow-up nor changes in enterolactone/genistein were associated with prognosis. Large long-term longitudinal studies with multiple phytoestrogen measurements are required to understand long-term effects of phytoestrogens after BC.

Topics: 4-Butyrolactone; Aged; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Cohort Studies; Female; Genistein; Germany; Humans; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Prognosis; Proportional Hazards Models; Prospective Studies; Survival Analysis; Survivors

Equol (EQ) is a prominent microbial metabolite of the soy isoflavone, daidzein, with estrogen-like properties. The major soy isoflavone, genistein (GEN), stimulated growth of estrogen-dependent breast cancer (EDBC) cells in vitro and tumor growth in vivo but EQ did not. To understand possible interactions of EQ and GEN on EDBC, EQ was used with GEN in combination in vitro and in vivo. Effects of EQ, GEN and EQ + GEN were evaluated using MCF-7 and T47D EDBC. Ovariectomized athymic mice were used as a model for in vivo tumor growth. Dietary EQ had no effect on MCF-7 tumor growth and the absence of effect was confirmed using a T47D EDBC in vivo model. EQ alone or in combination with GEN increased EDBC cell proliferation in vitro. EQ alone neither stimulated EDBC tumor growth in vivo at various doses nor suppressed tumor growth induced by dietary GEN. In summary, EQ has similar estrogenic effect as GEN in vitro but does not interact with GEN on EDBC tumor growth. Based on the evidence presented here, dietary EQ is unlikely to have estrogenic effects in vivo.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dietary Supplements; Equol; Female; Genistein; Humans; Mammary Glands, Animal; Mice, Inbred BALB C; Mice, Nude; Phytoestrogens

Accumulating evidence has shown that soy intake is associated with the promotion of health and prevention of cancers. However, the relationship between the intake of soy compounds and the risk of breast cancer is still debatable. In this study, we use mathematical models for assessing the impact of soy phytoestrogens and protein/peptide intervention on breast cancer development using the datasets acquired from a large number of published studies. We used data mining models, including the decision tree classification and association rule methods, to analyze 478 data collected from 201 research papers. The results indicated that the intervention of soy proteins and peptides, especially lunasin (LUN) and bowman-birk protease inhibitor (BBI), has a positive impact on different types of breast cancer, while the effects of soy phytoestrogens are inconsistent in breast cancer development. Among soy phytoestrogens, daidzein (DAI) exhibited the highest negative impact on breast cancer, followed by coumestrol (COU), soysapogenol (SAP), genistein (GEN), and equol (EQ). With regard to the type of cancer, phytoestrogens should be carefully considered in estrogen receptor (ER)+ or progesterone receptor (PR)+ breast cancer. In the case of ER-, PR- or triple negative type, both soy categories can be used as auxiliary interventions. In summary, this is the first study to use data mining to explore the relationship between the intake of soy phytoestrogens or proteins/peptides and breast cancer development. Our findings indicate that soy intervention might reduce breast cancer development. However, the specific soy compound and cancer type should be considered before allocating a precise nutrient intervention.

Topics: Antineoplastic Agents; Breast Neoplasms; Data Mining; Female; Humans; Phytoestrogens; Phytotherapy; Soybean Proteins

Breast cancer is a disease where cells in the tissue of the breast, grow and divide without normal control. Breast cancer is second major cause for death in world wide. Importance of natural product increase due to adverse effect of existing synthetic drugs.

Topics: Acetates; Antineoplastic Agents, Phytogenic; Asparagus Plant; Breast Neoplasms; Cell Line, Tumor; Computer Simulation; Drug Screening Assays, Antitumor; Estrogen Receptor alpha; Female; Humans; Molecular Docking Simulation; Phytoestrogens; Plant Extracts; Protein Conformation; Rutin; Solvents

Recently, strategies of cancer treatment using combination of agents with distinct molecular mechanism(s) of action are considered more promising due to its high efficacy and reduced systemic toxicity. The study is aimed to improve the efficacy of selective estrogen receptor modulator, Centchroman (CC) by combination with the phytoestrogen Genistein (GN).. Cytotoxicity was evaluated by Sulforhodamine B assay. Cell cycle analysis was done through flow cytometry. Further, Apoptosis was analyzed using Annexin V/PI staining, tunel assay and electron microscopic examination and verified using western blot analysis. In order to validate the in vitro results, in vivo analysis was performed using 4T1-syngeneic mouse model.. In this study, we report that the dietary isoflavone genistein (GN) synergistically improved antineoplasticity of CC in breast cancer by arresting cells at G2/M phase culminating in ROS dependent apoptosis. The combination of CC plus GN caused dysregulation of Bax and Bcl-2 ratio inducing mitochondrial dysfunction, activation of Caspase-3/7, -9 and PARP cleavage. Further, combination significantly suppresses phosphorylation of PI3K/Akt/NF-κB, enhancing apoptosis. Additionally, combination markedly reduced tumor growth compared to CC and GN alone in mouse 4T1 breast tumor model.. Together, these studies suggest that GN represents a potential adjunct molecule whose role in CC induced apoptosis deserves attention.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Survival; Centchroman; Drug Synergism; Female; Genistein; Humans; Isoflavones; MCF-7 Cells; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases; Phytoestrogens; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction

The soy isoflavone genistein has been described to up-regulate breast cancer resistance protein (BCRP) and, thus, enhance chemoresistance in breast cancer cells. The aim of this work was to assess the effect of long- and short-term incubation with daidzein, the second most abundant soy isoflavone and its metabolite equol on the expression and activity of P-glycoprotein, multidrug resistance-associated proteins 1 and 2 (MRP1 and MRP2) and BCRP in breast cancer cells.. MCF-7 and MDA-MB-231 cells were treated with phytoestrogen concentrations within the range achieved in individuals with a high isoflavone intake. Transporter expression was evaluated at protein and mRNA level through western blot and qRT-PCR, respectively. Transporter activity was determined using doxorubicin, mitoxantrone and carboxy-dichlorofluorescein as substrates.. Daidzein (5 µM) up-regulated MRP2- and down-regulated MRP1 protein expressions in MCF-7 and MDA-MB-231 cells, respectively. Both effects were ER-dependent, as determined using the antagonist ICI 182,780. The decrease in MRP1 mRNA in MDA-MB-231 cells indicates a transcriptional mechanism. On the contrary, MRP2 induction in MCF-7 cells takes place post-transcriptionally. Whereas changes in the transporter expression had a minor effect on the transporter activity, acute incubation with daidzein, R-equol and S-equol led to a strong inhibition of BCRP activity and an increase in the IC. In contrast to previous reports for genistein, daidzein and equol do not provoke a major up-regulation of the transporter expression but instead an inhibition of BCRP activity and sensitization to BCRP substrates.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Equol; Humans; Isoflavones; Neoplasm Proteins; Phytoestrogens; Polymerase Chain Reaction; Up-Regulation

Many breast cancer patients suffer from obvious side effects induced by chemotherapy. Formononetin (FM), one kind ingredient of Chinese herbal medicine, has been suggested to inhibit MCF-7 breast cancer cells. And recently metformin (MET) has gained more attention as a potential anti-cancer drug. The aim of this study was to investigate the synergistic effects of FM and MET on the proliferation of MCF-7 cells and to clarify the possible molecular mechanism involved. MCF-7 cells were treated with various concentrations of FM (40 and 80 μM) or FM (40 and 80 μM) combined with MET (150 μM) for 48 h. Cell proliferation was tested by an methyl tetrazolium (MTT) (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay. The percentage of apoptotic cells was measured by flow cytometry. The expression level of b-cell lymphoma/leukemia-2 (bcl-2) mRNA was examined by RT-PCR, while the expression levels of phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and bcl-2 protein were detected by Western blotting. Compared with untreated cells, 40 μM and 80 μM FM efficiently inhibited proliferation and increased apoptosis in MCF-7 cells. Additionally, 40 μM and 80 μM FM greatly downregulated bcl-2 mRNA expression when compared with untreated cells. Furthermore, the protein expression of bcl-2 and p-ERK1/2 was significantly reduced by 40 μM and 80 μM FM. The cytotoxic effect of FM was more remarkable when 150 μM MET was added. Taken together, the combinational use of FM and MET enhanced cell growth inhibition, and the induction of apoptosis in MCF-7 cells mediated by the ERK1/2 signaling pathway.

Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Drug Synergism; Female; Growth Inhibitors; Humans; Hypoglycemic Agents; Isoflavones; MCF-7 Cells; Metformin; Phytoestrogens

An increasing number of breast cancer patients in Asian countries has been found to consume dietary supplements including phytoestrogen-rich Chinese herbal medicines with an expectation to alleviate the side effects of conventional cancer therapies.. The question of whether estrogenic Chinese herbal medicines are beneficial or detrimental to the health of breast cancer patients remains uncertain.. The present study aimed at establishing a systematic approach to look at the safety profiles of estrogenic Chinese herbal medicines (CHM).. The effects of estrogenic CHM on the growth of human breast cancer cells as well as the progression of breast tumors in mice have been investigated.. Our results demonstrated that among 10 selected estrogenic CHM, the aqueous extracts of Cistanche deserticola (CD) and Dioscorea opposita (DO) at 0.4 to 1.6 mg/ml significantly stimulated cell viability in both estrogen receptor (ER)-positive (MDA-MB-361 and MCF-7) and ER-negative (SKBR3 and MDA-MB-231) breast cancer cells. However, results from animal studies showed that no significant difference was found on the size of mouse 4T1 breast tumors in CD- and DO-treated mice when compared with the control group, while the number of proliferative cells were found to be increased in DO-treated group. Besides, CD and DO treatments induced significant immunomodulatory effects on 4T1 tumor-bearing mice by increasing the production of cytokines IL-2 and IFN-γ and modulation of regulatory T-cells. Furthermore, CD and DO treatments did not stimulate, but in fact suppressed human triple-negative MDA-MB-231 breast xenografts growth in immunodeficiency mice.. The considerable concerns on the use of CD and DO in breast cancer patients could be relieved to some extents upon the findings of this pre-clinical study. The potential harmful effects of estrogenic Chinese herbal medicines on breast cancer growth should be verified in both cell-based and tumor-bearing mice models.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cistanche; Dioscorea; Drugs, Chinese Herbal; Female; Humans; Mice, Inbred BALB C; Mice, SCID; Phytoestrogens; Xenograft Model Antitumor Assays

The flavone apigenin and the mycotoxin zearalenone are two major compounds found in the human diet which bind estrogen receptors (ERs), and therefore influence ER activity. However, the underlying mechanisms are not well known. To unravel the molecular mechanisms that could explain the differential effect of zearalenone and apigenin on ER-positive breast cancer cell proliferation, gene-reporter assays, chromatin immunoprecipitation (ChIP) experiments, proliferation assays and transcriptomic analysis were performed. We found that zearalenone and apigenin transactivated ERs and promoted the expression of estradiol (E2)-responsive genes. However, zearalenone clearly enhanced cellular proliferation, while apigenin appeared to be antiestrogenic in the presence of E2 in both ER-positive breast cancer cell lines, MCF-7 and T47D. The transcriptomic analysis showed that both compounds regulate gene expression in the same way, but with differences in intensity. Two major sets of genes were identified; one set was linked to the cell cycle and the other set was linked to stress response and growth arrest. Our results show that the transcription dynamics in gene regulation induced by apigenin were somehow different with zearalenone and E2 and may explain the differential effect of these compounds on the phenotype of the breast cancer cell. Together, our results confirmed the potential health benefit effect of apigenin, while zearalenone appeared to be a true endocrine-disrupting compound.

Topics: Apigenin; Breast Neoplasms; Cell Line, Tumor; Estrogens, Non-Steroidal; Female; Humans; Phytoestrogens; Receptors, Estrogen; Zearalenone

Breast cancer is the most common malignancy in women of developed countries. The aim of this study was to investigate the effects of the phytoestrogen genistein on the inflammatory profile in three breast cancer cell lines with different oestrogen receptors alpha (ERα) and beta (ERβ) ratio. MCF-7 (high ERα/ERβ ratio), T47D (low ERα/ERβ ratio), and MDA-MB-231 (ERα-negative) cells were treated with 1 µM of genistein for 48 h (cell proliferation and ROS production) or 4 h (mRNA expression of 18S, ERα, ERβ, pS2, Sirtuin1, IL-1β, NF-κB, COX-2, TGFβ1, PPARγ). Genistein caused a significant decrease in cell viability and an increase in ROS production in MCF-7, and the opposite happens in T47D cells. In addition, genistein rise pro-inflammatory and reduced anti-inflammatory genes expression in MCF-7, provoking the opposite effects in T47D cells. In conclusion, the phytoestrogen genistein could modulate the expression of inflammatory-related genes through its interaction with both ERs, and its effects depends on the ERα/ERβ ratio.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genistein; Humans; Inflammation; MCF-7 Cells; Phytoestrogens; Reactive Oxygen Species

To explore the ex vivo effects of phytoestrogens on primary human breast cancer cells.. Breast cancer cells were obtained from patients who underwent primary breast cancer surgery, which were treated with 10. Human breast cancer cell viability was inhibited by all phytoestrogens but induced by E. In the presence of E

Topics: Antineoplastic Agents, Hormonal; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genistein; Humans; Phytoestrogens; Quercetin; Resveratrol

High intakes of the phytoestrogen lignans and high blood concentrations of its main biomarker, enterolactone, has been associated with a better breast cancer prognosis. We investigated the association between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis (i.e. recurrence, breast cancer-specific mortality and all-cause mortality).. Plasma and data was available from the Danish Diet, Cancer and Health cohort. Information on treatment and clinical characteristics from registries and clinical databases and both pre-diagnostic and diagnostic plasma measurement of enterolactone on a sub-set. Enterolactone was quantified in plasma using a high-throughput LC-MS/MS method. We followed 1457 breast cancer cases from date of diagnosis and until censoring or end-of-follow-up (median 9 years), during this time 404 died (250 of breast cancer) and 267 experienced recurrence. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI).. Plasma enterolactone were borderline significantly associated with lower breast cancer-specific mortality (HR. Overall, no clear association was found between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis.

Topics: 4-Butyrolactone; Aged; Breast Neoplasms; Cohort Studies; Denmark; Female; Humans; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Prognosis

Recently, the palbociclib/letrozole combination therapy was granted accelerated US FDA approval for the treatment of estrogen receptor (ER)-positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein and the estrogenic mycotoxin zearalenone. A global metabolomics approach was applied to unravel metabolite and pathway modifications. The results clearly showed that the combined effects of palbociclib and letrozole on cellular metabolism were far more pronounced than that of each agent alone and potently influenced by xenoestrogens. This behavior was confirmed in proliferation experiments and functional assays. Specifically, amino acids and central carbon metabolites were attenuated, while higher abundances were observed for fatty acids and most nucleic acid-related metabolites. Interestingly, exposure to model xenoestrogens appeared to counteract these effects.

Topics: Breast Neoplasms; Carbon; Diet; Female; Genistein; Humans; Letrozole; MCF-7 Cells; Metabolome; Metabolomics; Phytoestrogens; Piperazines; Principal Component Analysis; Pyridines; Receptors, Estrogen; Zearalenone

Breast cancer is a highly heterogeneous disease influenced by the hormonal microenvironment and the most common malignancy in women worldwide. Some phytoestrogens and mycoestrogens have been epidemiologically linked as risk factors or protectors, however their mechanisms of action are complex and not fully understood. The aim of this study was to predict the potential of 36 natural xenoestrogens to interact with 189 breast cancer proteins using AutoDock Vina. In order to validate our protocol, an in silico docking pose and binding site determination was compared with the crystallographic structure and the power of prediction to distinguish between ligand and decoys was evaluated through a receiver operating characteristic curve (ROC) of the resultant docking affinities and in vitro data. The best affinity score was obtained for glyceollin III interacting with the sex hormone binding globulin (-11.9 Kcal/mol), a plasma steroid transport protein that regulates sex steroids bioavailability. Other natural xenoestrogens such as beta-carotene, chrysophanol 8-O-beta-d-glucopyranoside and glyceollin I, also presented good affinity for proteins related to this disease and the validation was successful. This study may help to prioritize compounds for toxicity tests or drug development from natural scaffolds, and to elucidate their mechanisms of action.

Topics: Breast Neoplasms; Computer Simulation; Endocrine Disruptors; Fungi; Molecular Docking Simulation; Neoplasm Proteins; Phytoestrogens; Protein Binding; Protein Conformation

Estrogen receptors (ERs) α and β are distributed in most tissues of women and men. ERs are bound by estradiol (E2), a natural hormone, and mediate the pleiotropic and tissue-specific effects of E2, such as proliferation of breast epithelial cells or protection and differentiation of neuronal cells. Numerous environmental molecules, called endocrine disrupting compounds, also interact with ERs. Phytoestrogens belong to this large family and are considered potent therapeutic molecules that act through their selective estrogen receptor modulator (SERM) activity. Using breast cancer cell lines as a model of estrogen-dependent proliferation and a stably ER-expressing PC12 cell line as a model of neuronal differentiating cells, we studied the SERM activity of major dietary compounds, such as apigenin, liquiritigenin, daidzein, genistein, coumestrol, resveratrol and zearalenone. The ability of these compounds to induce ER-transactivation and breast cancer cell proliferation and enhance Nerve Growth Factor (NGF) -induced neuritogenesis was assessed. Surprisingly, although all compounds were able to activate the ER through an estrogen responsive element reporter gene, they showed differential activity toward proliferation or differentiation. Apigenin and resveratrol showed a partial or no proliferative effect on breast cancer cells but fully contributed to the neuritogenesis effect of NGF. However, daidzein and zearalenone showed full effects on cellular proliferation but did not induce cellular differentiation. In summary, our results suggest that the therapeutic potential of phytoestrogens can diverge depending on the molecule and the phenotype considered. Hence, apigenin and resveratrol might be used in the development of therapeutics for breast cancer and brain diseases.

Topics: Adrenal Gland Neoplasms; Animals; Antineoplastic Agents, Phytogenic; Apigenin; Breast Neoplasms; Cell Proliferation; Chemokine CXCL12; Diet; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; MCF-7 Cells; Nerve Tissue Proteins; Neurites; Neurogenesis; PC12 Cells; Pheochromocytoma; Phytoestrogens; Rats; Response Elements; Resveratrol; Selective Estrogen Receptor Modulators; Stilbenes; Transcription, Genetic; Transfection; Zearalenone

Diarylheptanoids from Curcuma comosa, of the Zingiberaceae family, exhibit diverse estrogenic activities. In this study we investigated the estrogenic activity of a major hydroxyl diarylheptanoid, 7-(3,4 -dihydroxyphenyl)-5-hydroxy-1-phenyl-(1E)-1-heptene (compound 092) isolated from C. comosa. The compound elicited different transcriptional activities of estrogen agonist at low concentrations (0.1-1 μM) and antagonist at high concentrations (10-50 μM) using luciferase reporter gene assay in HEK-293T cells. In human breast cancer (MCF-7) cells, compound 092 showed an anti-estrogenic activity by down-regulating ERα-signaling and suppressing estrogen-responsive genes, whereas it attenuated the uterotrophic effect of estrogen in immature ovariectomized rats. Of note, compound 092 promoted mouse pre-osteoblastic (MC3T3-E1) cell differentiation and the related bone markers, indicating its positive osteogenic effect. Our findings highlight a new, nonsteroidal, estrogen agonist/antagonist of catechol diarylheptanoid from C. comosa, which is scientific evidence supporting its potential as a dietary supplement to prevent bone loss with low risk of breast and uterine cancers in postmenopausal women.

Topics: 3T3 Cells; Animals; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Curcuma; Diarylheptanoids; Estrogen Receptor alpha; Female; Humans; Mice; Osteoblasts; Phytoestrogens; Plant Extracts; Rats; Rats, Wistar; Selective Estrogen Receptor Modulators; Uterus

EXECUTIVE SUMMARY This American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) Position Statement is designed to update the previous menopause clinical practice guidelines published in 2011 but does not replace them. The current document reviews new clinical trials published since then as well as new information regarding possible risks and benefits of therapies available for the treatment of menopausal symptoms. AACE reinforces the recommendations made in its previous guidelines and provides additional recommendations on the basis of new data. A summary regarding this position statement is listed below: New information available from randomized clinical trials and epidemiologic studies reported after 2011 was critically reviewed. No previous recommendations from the 2011 menopause clinical practice guidelines have been reversed or changed. Newer information enhances AACE's guidance for the use of hormone therapy in different subsets of women. Newer information helps to support the use of various types of estrogens, selective estrogen-receptor modulators (SERMs), and progesterone, as well as the route of delivery. Newer information supports the previous recommendation against the use of bioidentical hormones. The use of nonhormonal therapies for the symptomatic relief of menopausal symptoms is supported. Newer information enhances AACE's guidance for the use of hormone therapy in different subsets of women. Newer information helps to support the use of various types of estrogens, SERMs, and progesterone, as well as the route of delivery. Newer information supports the previous recommendation against the use of bioidentical hormones. The use of nonhormonal therapies for the symptomatic relief of menopausal symptoms is supported. New recommendations in this position statement include: 1.. the use of menopausal hormone therapy in symptomatic postmenopausal women should be based on consideration of all risk factors for cardiovascular disease, age, and time from menopause. 2.. the use of transdermal as compared with oral estrogen preparations may be considered less likely to produce thrombotic risk and perhaps the risk of stroke and coronary artery disease. 3.. when the use of progesterone is necessary, micronized progesterone is considered the safer alternative. 4.. in symptomatic menopausal women who are at significant risk from the use of hormone replacement therapy, the use of selective serotonin re-uptake inhibitors and possibly other nonhormonal agents may offer significant symptom relief. 5.. AACE does not recommend use of bioidentical hormone therapy. 6.. AACE fully supports the recommendations of the Comité de l'Évolution des Pratiques en Oncologie regarding the management of menopause in women with breast cancer. 7.. HRT is not recommended for the prevention of diabetes. 8.. In women with previously diagnosed diabetes, the use of HRT should be individualized, taking in to account age, metabolic, and cardiovascular risk factors.. AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; BMI = body mass index; CAC = coronary artery calcification; CEE = conjugated equine estrogen; CEPO = Comité de l'Évolution des Pratiques en Oncologie; CAD = coronary artery disease; CIMT = carotid intima media thickness; CVD = cardiovascular disease; FDA = Food and Drug Administration; HDL = high-density lipoprotein; HRT = hormone replacement therapy; HT = hypertension; KEEPS = Kronos Early Estrogen Prevention Study; LDL = low-density lipoprotein; MBS = metabolic syndrome; MPA = medroxyprogesterone acetate; RR = relative risk; SERM = selective estrogen-receptor modulator; SSRI = selective serotonin re-uptake inhibitor; VTE = venous thrombo-embolism; WHI = Women's Health Initiative.

Topics: Administration, Cutaneous; Administration, Oral; Aged; Amines; Breast Neoplasms; Cardiovascular Diseases; Cimicifuga; Cognition; Cyclohexanecarboxylic Acids; Diabetes Mellitus; Endocrinology; Estradiol; Estrogen Replacement Therapy; Estrogens; Excitatory Amino Acid Antagonists; Female; Gabapentin; gamma-Aminobutyric Acid; Hot Flashes; Humans; Menopause; Middle Aged; Osteoporosis; Phytoestrogens; Phytotherapy; Progesterone; Progestins; Risk Assessment; Selective Serotonin Reuptake Inhibitors; Societies, Medical; Thrombosis; Vasomotor System

The study is aimed at evaluating the chemosensitization and apoptotic effect of aglycone rich extracts of dietary phytoestrogens (derived from soybean and flaxseed) on estrogen receptor positive, MCF-7 and estrogen receptor negative, MDA-MB-231 cells. The extracts show potent activity on both the cell lines, hence, in silico studies have been carried out to find the possible reason for their activity.. MTT assay was carried to assess chemosensitization effect and activated caspase-3/7 activity was studied using flow-cytometry and western blotting. In silico studies were carried out using PharmMapper and the top hits were taken up for docking using the Schrödinger software. Top molecular targets were subjected to gene expression studies by qPCR and protein expression using Western blot analysis.. This study reports the apoptotic activity and chemosensitization effect of the phytoestrogens. Molecular docking studies predict AKR1B1 (aldose reductase), HRAS (Harvey rat sarcoma) and GSTP1 (glutathione s-transferase pi) as potential molecular targets for genistein, daidzein and secoisolariciresinol, respectively. Gene and protein expression studies show down-regulation of AKR1BI, HRAS and GSTP1 by the extracts.. The qPCR and western blot analysis results support the computational analyses, and hence genistein, daidzein and secoisolariciresinol may be considered as good candidates for future development into potent inhibitors of the respective protein targets through medicinal chemistry optimization.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Breast Neoplasms; Butylene Glycols; Caspase 3; Caspase 7; Cell Line, Tumor; Computer Simulation; Down-Regulation; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Genistein; Humans; Isoflavones; Lignans; MCF-7 Cells; Molecular Docking Simulation; Phytoestrogens

Phytoestrogens (PE) may improve breast cancer prognosis by modifying tumor prognostic markers, such as cell proliferation marker Ki-67 and human epidermal growth factor receptor 2 (HER2). Epidemiological evidence linking lignans and isoflavones to Ki-67 and HER2 is limited. We examined associations between the major metabolites of lignans and isoflavones - enterolactone (ENL) and genistein (GEN) - respectively, and Ki-67 expression and HER2 in tumor tissue of breast cancer patients.. Data from 1060 invasive breast cancer patients from the population-based MARIE study were used. Multivariate-adjusted linear (Ki-67 log-transformed) and quantile regression, and logistic regression analyses (HER2, Ki-67 dichotomized) were performed to calculate β estimates and ORs, respectively. Median post-diagnostic ENL and GEN concentrations were 19.5 and 4.8 nmol/L, respectively. Median Ki-67 was 12.0%, and 21.2% of the tumors were HER2+. After adjustment, there was an inverse association between GEN and Ki-67 at high expression levels (OR for Ki-67 ≥20% versus <20% of 0.93 (95%CI [0.87;0.99]) per 10 nmol/L GEN increment).. Our findings indicate an inverse association between GEN and Ki-67 at high levels of Ki-67 expression. Additional investigations are recommended to confirm our findings and to further elucidate mechanisms linking PE metabolites to breast cancer survival.

Topics: 4-Butyrolactone; Aged; Breast Carcinoma In Situ; Breast Neoplasms; Case-Control Studies; Cell Proliferation; Female; Genistein; Germany; Humans; Isoflavones; Ki-67 Antigen; Lignans; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Phytoestrogens; Postmenopause; Prognosis; Receptor, ErbB-2; Tumor Burden

As a phytoestrogen, 3,3'-diindolylmethane (DIM) plays a chemopreventive role by inhibiting cancer progression. In this study, we examined the effects of 17β-estradiol (E2), two endocrine disrupting chemicals (EDCs), triclosan (TCS) and bisphenol A (BPA), and DIM on epithelial-mesenchymal transition (EMT) and metastatic behaviors of estrogen receptor (ER)-positive MCF-7 breast cancer cells. An in vitro assay revealed that E2 (10

Topics: Animals; Benzhydryl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Endocrine Disruptors; Female; Heterografts; Humans; Indoles; Mice; Mice, Inbred BALB C; Phenols; Phytoestrogens; Receptors, CXCR4; Signal Transduction

Topics: Binding Sites; Breast Neoplasms; Dimerization; Estradiol; Estrogen Receptor alpha; Female; Humans; MCF-7 Cells; Phytoestrogens; Protein Binding; Spectrophotometry, Atomic; Thiazines; Transcription Factor AP-1; Transcription, Genetic

As a phytoestrogen, kaempferol is known to play a chemopreventive role inhibiting carcinogenesis and cancer progression. In this study, the influences of triclosan, an anti-bacterial agent recently known for an endocrine disrupting chemical (EDC), and kaempferol on breast cancer progression were examined by measuring their effects on epithelial-mesenchymal transition (EMT) and metastatic-related behaviors of MCF-7 breast cancer cells. Morphological changes of MCF-7 cells were observed, and a wound-healing assay was performed after the treatment of triclosan and kaempferol. The effects of triclosan and kaempferol on protein expression of EMT-related markers such as E-cadherin, N-cadherin, Snail, and Slug and metastasis-related markers such as cathepsin B, D, MMP-2 and -9 were investigated by Western blot assay. In microscopic observations, triclosan (10

Topics: Anti-Infective Agents, Local; Antineoplastic Agents; Breast Neoplasms; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Kaempferols; MCF-7 Cells; Neoplasm Invasiveness; Phytoestrogens; Receptors, Estrogen; Triclosan

Phytoestrogens have controversial effects on hormone-dependent tumors. Herein we investigated the effects of parsley root extract (PCE) on DNA synthesis performance, metabolic activity and cytotoxicity in malignant and benign breast cells.. The PCE was prepared and analyzed by mass spectrometry. MCF7 and MCF12A cells were incubated with various concentrations of PCE and analyzed for DNA synthesis performance, metabolic activity and cytotoxicity by BrdU proliferation, MTT and LDH assays, respectively.. PCE was found to contain a substantial ratio of lignans. At a concentration range of 0.01 μg/ml-100 μg/ml the LDH assay analysis showed no significant cytotoxicity of PCE in both cell lines. However, at 500 μg/ml PCE's cytotoxicity was well over 70% of total cell population in both cell lines. According to the BrdU proliferation assay analysis, PCE demonstrated significant DNA synthesis inhibition of up to 80% at concentrations of 10, 50, 100 and 500 μg/ml in both cell lines. Based on the MTT assay analysis, only at a concentration of 500 μg/ml, PCE demonstrated a statistically significant inhibition of cellular metabolic activity of 63% in MCF7 and 75% in MCF12A of their respective normal capacity.. PCE showed antiproliferative effects in MCF7 and MCF12A cells. Further investigation is required to determine whether this effect can be solely attributed to its phytoestrogens.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Proliferation; Cell Survival; DNA Replication; Dose-Response Relationship, Drug; Energy Metabolism; Female; Humans; Immunohistochemistry; Mammary Glands, Human; Mass Spectrometry; MCF-7 Cells; Petroselinum; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Roots; Plants, Medicinal; Receptors, Estrogen

Arctigenin is a plant lignan extracted from Arctium lappa that has been shown to have estrogenic properties. In spite of the health benefits of phytoestrogens reducing the risk of osteoporosis, heart disease, and menopausal symptoms, its benefits against the risk of breast cancer have not been fully elucidated. Thus, we investigated the effects of arctigenin on metastasis of breast cancer using both estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, arctigenin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and invasion. The activity of crucial metastatic protease matrix metalloprotease (MMP)-9 in gelatin zymography was also efficiently decreased by arctigenin, as well as its mRNA expression. Notably, arctigenin exhibited similar anti-metastatic effects even in ER-negative MDA-MB-231 cells, suggesting that the anti-metastatic effects of arctigenin were not exerted via the ER. The upstream signaling pathways involved in the regulation of MMP-9 and urokinase plasminogen activator (uPA) were analyzed using western blotting. The activation of Akt, NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be inhibited. Taken together, these data suggest that arctigenin confers anti-metastatic effects by inhibiting MMP-9 and uPA via the Akt, NF-κB and MAPK signaling pathways on breast cancer, regardless of ER expression. Therefore, we propose that the intake of arctigenin could be an effective supplement for breast cancer patients.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Furans; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Lignans; Matrix Metalloproteinase 9; MCF-7 Cells; Neoplasm Metastasis; Phytoestrogens; Receptors, Estrogen; Signal Transduction; Urokinase-Type Plasminogen Activator

Formononetin is an O-methylated isoflavone that is isolated from the root of Astragalus membranaceus, and it has antitumorigenic effects. Our previous studies found that formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. To further investigate the potential effect of formononetin in promoting cell proliferation in estrogen receptor (ER)-positive cells, we used in vivo and in vitro studies to elucidate the possible mechanism. ERα-positive cells (HUVEC, MCF-7) were treated with formononetin. The CCK8 assay, Hoechst 33258, and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. ERα, p-Akt, and Bcl-2 expression was determined using Western blot. Compared with the control, low formononetin concentrations (2-6 μM) stimulated ERα-positive cell proliferation (HUVEC, MCF-7). The more sensitive HUVEC cells were used to study the relevant signaling pathway. After treatment with formononetin, ERα, miR-375, p-Akt, and Bcl-2 expression was significantly upregulated. The proliferative effect of formononetin was also blocked by a miR-375 inhibitor or raloxifene pretreatment. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with formononetin increased significantly, but the weight dramatically decreased with raloxifene or miR-375 inhibitor pretreatment before formononetin. This study demonstrated that formononetin promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Astragalus propinquus; Breast Neoplasms; Cell Proliferation; Estrogen Receptor alpha; Female; Human Umbilical Vein Endothelial Cells; Humans; Isoflavones; MCF-7 Cells; Mice; MicroRNAs; Phytoestrogens; Signal Transduction

Genistein (GEN) is a phytoestrogen found in soybeans. GEN exerts its functions through its interaction with the estrogen receptors (ER), ERα and ERβ, and we previously reported that the ERα/ERβ ratio is an important factor to consider in GEN-treated breast cancer cells. The aim of this study was to investigate the effects of GEN in breast cancer cells with different ERα/ERβ ratio: MCF-7 (high ratio), T47D (low ratio), and MCF-7 overexpressing ERβ (MCF7 + ERβ) treated with cisplatin (CDDP), paclitaxel (PTX) or tamoxifen (TAM). Cell viability, ROS production, autophagy, apoptosis, antioxidant enzymes protein levels, and cell cycle were analyzed. GEN treatment provoked an increase in cell viability in MCF-7 cells and in the antioxidant enzymes protein levels in combination with the cytotoxic agents, decreasing ROS production (CDDP + GEN and TAM+GEN) and autophagy (TAM + GEN) or apoptosis (CDDP + GEN and TAM + GEN). Moreover GEN treatment enhanced the cell cycle S phase entry in CDDP+GEN- and TAM + GEN-treated MCF-7 cells and, in the case of CDDP + GEN, increased the proportion of cells in the G2/M phase and decreased it in the subG0 /G1 phase. Otherwise, in the T47D and MCF7 + ERβ cells the combination of GEN with cytotoxic treatments did not cause significant changes in these parameters, even TAM + GEN-treated T47D cells showed less cell viability due to an increment in the autophagy. In conclusion, GEN consumption may be counterproductive in those patients receiving anticancer treatment with a high ERα/ERβ ratio diagnosed breast cancer and it could be harmless or even beneficial in those patients with a lower ERα/ERβ ratio breast cancer cells.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genistein; Humans; MCF-7 Cells; Phytoestrogens

It is believed that breast cancer stem cells (BCSCs), like normal stem cell counterparts, have the capacity of self-renewal and differentiation. Simultaneously, estrogen receptor (ER)-negative (-) BCSCs are affected by surrounding differentiated ER-positive (+) tumor cells by virtue of paracrine signaling within the tumor micro-environment. Genistein (GEN), as a sort of phytoestrogen, can act on ER+ breast cancer cells but the role of GEN in the differentiation of neighboring ER- BCSCs has not been defined. Transwell co-culture system was utilized so as to elaborate the interaction between well-differentiated ER+ breast cancer cells (MCF-7) and ER- breast cancer stem/progenitor cells (mammospheres derived from MDA-MB-231 cells). GEN-induced differentiation of BCSCs was analyzed by mammospheres formation assay, flow cytometry and RT-PCR after a 3 day solo-culture or co-culture. We find that GEN sized 2 µM, and 40 nM, effectively promotes morphological alteration of mammospheres, reduces the ratio of subset of CD44+/CD24-/ESA+ cells and upregulates the expression of differentiated cell markers of mammospheres in co-culture system, but not in solo-culture condition. Besides, we demonstrate that the differentiation-inducing effect of GEN on mammospheres is associated with PI3K/Akt and MEK/ERK signaling pathways which are activated by amphiregulin released from ER+ cancer cells. These results indicate that GEN was able to induce the differentiation of breast cancer stem/progenitor cells through interaction with ER+ cancer cells by a paracrine mechanism.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Culture Media, Conditioned; Estradiol; Estrogen Receptor alpha; Female; Flow Cytometry; Genistein; Humans; MCF-7 Cells; Neoplastic Stem Cells; Paracrine Communication; Phytoestrogens; Signal Transduction; Stem Cells; Tumor Microenvironment

Breast cancer is the most frequent malignancy in women. Multidrug resistance due to overexpression of ABC drug transporters is a common cause of chemotherapy failure and disease recurrence. Genistein (GNT) is a phytoestrogen present in soybeans and hormone supplements. We investigated the effect of GNT on the expression and function of ABC transporters in MCF-7 and MDA-MB-231 breast cancer cell lines. Results demonstrated an induction at the protein level of ABCC1 and ABCG2 and of ABCC1 in MCF-7 and MDA-MB-231, respectively. MCF-7 cells showed a concomitant increase in doxorubicin and mitoxantrone efflux and resistance, dependent on ABCG2 activity. ABCC1 induction by GNT in MDA-MB-231 cells modified neither drug efflux nor chemoresistance due to simultaneous acute inhibition of the transporter activity by GNT. All inductions took place at the translational level, as no increment in mRNA was observed and protein increase was prevented by cycloheximide. miR-181a, already demonstrated to inhibit ABCG2 translation, was down-regulated by GNT, explaining translational induction. Effects were independent of classical estrogen receptors. Results suggest potential nutrient-drug interactions that could threaten chemotherapy efficacy, especially in ABCG2-expressing tumors treated with substrates of this transporter.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Breast Neoplasms; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Food-Drug Interactions; Gene Expression Regulation, Neoplastic; Genistein; Humans; MCF-7 Cells; MicroRNAs; Mitoxantrone; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Phytoestrogens; Protein Biosynthesis; Protein Synthesis Inhibitors; Risk Assessment; Up-Regulation

Exposure to sex steroids increases the risk of breast cancer but the exact mechanisms are yet to be elucidated. Events in the microenvironment are important for carcinogenesis. Diet containing phytoestrogens can affect the breast microenvironment and alter the risk of breast cancer. It has previously been shown that estrogen regulates extracellular levels of leptin, adiponectin, and VEGF in normal breast tissue in vivo. Whether these proteins correlate in breast tissue in vivo or if diet addition of flaxseed, a major source of phytoestrogens in Western diets, alters adipokine levels in breast tissue are unknown. We used microdialysis to sample proteins of normal human breast tissue and abdominal subcutaneous fat in situ in 34 pre-and postmenopausal women. In vitro, co-culture of breast cancer cells and primary human adipocytes was used. In vivo, in normal breast tissue, a significant positive correlation between VEGF and leptin was detected. No correlations were found in fat tissue. Co-culture of adipocytes and breast cancer cells per se increased the secretion of VEGF and leptin and enhanced the effects of estradiol compared to culture of either cell type alone. In vitro, inhibition of VEGF diminished the release of leptin while inhibition of leptin had no influence on VEGF secretion. The levels of leptin decreased and adiponectin increased after a dietary addition of 25 g of flaxseed/day for one menstrual cycle. We conclude that VEGF and leptin correlate significantly in normal human breast tissue in vivo and that dietary addition of flaxseed affect adipokine levels in the breast.

Topics: Adenocarcinoma; Adipokines; Adult; Antineoplastic Agents, Phytogenic; Breast; Breast Neoplasms; Cells, Cultured; Coculture Techniques; Dietary Supplements; Female; Flax; Humans; MCF-7 Cells; Microdialysis; Middle Aged; Organ Specificity; Phytoestrogens; Postmenopause; Premenopause; Seeds; Subcutaneous Fat, Abdominal; Vascular Endothelial Growth Factors

Consumption of virgin olive oil (VOO) has been associated with a low breast cancer incidence. Pinoresinol is a phytoestrogen that is typically found in VOO. Considering the role of oestrogen in breast cancer development and progression, we investigated the potential antitumor activity of pinoresinol in breast cancer cells.. To address this question, we treated MDA-MB-231 (oestrogen receptor [ER] negative) and MCF7 (ER+) human breast tumour cells and MCF10A human mammary epithelial cells (ER-) with different concentrations of pinoresinol. The cytotoxic activity, cell proliferation, cell cycle profile, apoptosis induction, reactive oxygen species production and DNA damage were assessed.. Pinoresinol showed cytotoxic, anti-proliferative and pro-oxidant activity in human breast tumour cells, independent of their oestrogen receptor status. In addition, pinoresinol exerted antioxidant activity and prevented DNA damage associated with oxidative stress in human mammary epithelial cells.. Overall, the results suggest that pinoresinol may have antitumor activity in human breast cancer cells independently of oestrogen receptor status. Furthermore, the results show that the pinoresinol has the typical characteristics of a chemopreventive compound.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Furans; Humans; Lignans; Olive Oil; Phytoestrogens; Receptors, Estrogen

Phytoestrogens are known for their physiological role in lowering risk of osteoporosis, heart disease, breast cancer and menopausal symptoms. They are plant derived potent anti-oxidants, but tend to show pro-oxidant effect at higher concentrations. This study has been undertaken to exploit their pro-oxidant effect in the management of cancer. Cancer cells inherently possess high intracellular ROS levels, however, these levels do not cause harm to the cancer cells because of the anti-oxidant enzyme system. So, there is a need for a treatment strategy which could modulate the ROS levels. Breast cancer cell lines MCF-7 and MDA-MB-231 are treated with various concentrations of soyabean aglycone rich extracts (SARE) and flaxseed aglycone rich extracts (FSARE). The treatment brings about a significant decrease in super oxide dismutase (SOD) and glutathione peroxidase (GPx) activity, thereby leading to accumulation of superoxide ion and peroxide in the cells. The catalase (CAT) activity however, did not show a dose dependent change. The intra-cellular reactive oxygen species (ROS) levels increased and a marked change in mitochondrial membrane potential was detected. Cell cycle arrest was seen at S and G2/M phase in MCF-7 cells and high accumulation of cells in Sub G1 phase was seen in MDA-MB-231 cells. Microscopic evaluation indicated apoptotic morphology and DNA damage. This study suggests an important role of soyabean and flaxseed aglycones in modulating intracellular ROS in breast carcinoma.

Topics: Breast Neoplasms; DNA Damage; Dose-Response Relationship, Drug; Female; Flax; Glycine max; Humans; MCF-7 Cells; Phytoestrogens; Plant Extracts; Reactive Oxygen Species

Genistein can prevent tumorigenesis and reduce the incidence of diseases that are dependent upon estrogen. Previous research, however, has shown that genistein can also increase the risk of breast cancer. Thus, the aim of the present study was to investigate the mechanism underlying the effect of genistein in breast cancer and to determine whether genistein produces a therapeutic effect or promotes the development of breast cancer. Gene microarray data obtained from three samples treated with alcohol (control group), three samples treated with 3 µmol/l genistein and three samples treated with 10 µmol/l genistein for 48 h, were downloaded from the Gene Expression Omnibus database. Analysis of the differentially expressed genes (DEGs) and functional enrichment in the two genistein groups was performed. The interaction networks of the DEGs were constructed and the overlapping network was extracted. Finally, the functions and pathways of the DEGs in the overlapping network were enriched. In total, 224 DEGs coexisted in the two genistein groups, and the most significant function of these was the cell cycle. The number and the fold change of expression values of the DEGs in the 10 µmol/l genistein group were significantly higher compared with that of the 3 µmol/l genistein group. The most significant function and pathway of the DEGs in the overlapping network was the cell cycle involving several genes, including GLIPR1, CDC20, BUB1, MCM2 and CCNB1. Thus, genistein stimulation resulted in gene expression changes in breast cancer cell lines and discrepancies increased with higher doses of genistein. The DEGs were most significantly associated with cell cycle regulation.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cluster Analysis; Computational Biology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genistein; Humans; Phytoestrogens; Protein Kinase Inhibitors; Signal Transduction

Lignans, a class of phytoestrogen commonly found in the Western diet, have been linked to decreased breast cancer risks in epidemiologic studies. Similar to estrogen receptors, the androgen receptor (AR), a prognostic factor in breast tumors, may be affected by lignans. However, few studies have investigated this link in the context of breast cancer etiology. We evaluated the relationship between dietary lignan intake and AR expression in incident breast tumors.. Tumor tissue, epidemiological, and clinical data were collected from 216 women with incident, primary, histologically confirmed breast cancer enrolled in the Roswell Park Cancer Institute (RPCI) Data Bank and BioRepository (DBBR). On average, three tumor cores from each participant were assembled into a tissue micro array. After immunohistochemical staining, a trained RPCI pathologist determined AR status of each core. Lignan intake was calculated from a food frequency questionnaire collected upon enrollment into the DBBR.. We observed a weak positive association between dietary lignans and AR expression [β (SE) 27.6 (17.0), p 0.10], and there was no significant difference in lignan intake across categories of AR expression (p = 0.09, R (2) = 0.35).. Our results do not support a clear relationship between dietary lignan intake and AR expression. This investigation is the first, to our knowledge, to examine dietary lignan intake and AR expression in breast tumors. Further research is needed within a larger, more representative sample to determine whether lignan intake is truly associated with AR expression.

Topics: Adult; Aged; Androgens; Body Mass Index; Breast Neoplasms; Diet; Feeding Behavior; Female; Humans; Immunohistochemistry; Lignans; Middle Aged; Phytoestrogens; Receptors, Androgen; Receptors, Estrogen; Tissue Array Analysis

We examined the phytoestrogenic effects of palmiwon on breast carcinoma, lipid accumulation in methyl-β-cyclodextrin-induced HepG2 cells, and lipid-related diseases in a rat model of menopausal hyperlipidemia.. E-Screen assay was used to screen for phytoestrogens, especially those with antiestrogenic activity, in MCF-7 cells. Oil Red O staining and intracellular cholesterol analyses were used to quantify cellular cholesterol levels. 3-Hydroxy-3-methyl glutaryl coenzyme A reductase assay was used to measure enzyme activity. The levels of phosphorylated adenosine monophosphate-activated protein kinases and products of genes involved in cholesterol synthesis were measured by Western blot analysis. Thirty rats were either ovariectomized or sham-operated and randomly assigned to four groups (n = 5)-Sham, OVX, OVX-SV, or OVX-PMW (50, 150, or 450 mg/kg) group-for 8 weeks. A number of targets associated with lipid-related diseases were examined to confirm the estrogenic effects of palmiwon.. Palmiwon showed antiestrogenic activity in MCF-7 cells. Palmiwon decreased lipid accumulation, total cholesterol levels, and low-density lipoprotein/very-low-density lipoprotein levels in HepG2 cells. Moreover, palmiwon reversed the effects of methyl-β-cyclodextrin on cholesterol synthesis regulators and inhibited the activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase. Phosphorylation of adenosine monophosphate-activated protein kinase was stimulated by palmiwon. In ovariectomized rats, palmiwon reduced retroperitoneal and perirenal fat accumulation, serum lipids, atherogenic index, cardiac risk factor score, intima-media thickness, and nonalcoholic steatohepatitis scores.. These results indicate that palmiwon inhibits lipid accumulation without estrogenic activity in the breast. Therefore, palmiwon may have potential as a therapeutic agent for the treatment of hyperlipidemia in postmenopausal women.

Topics: Animals; beta-Cyclodextrins; Breast Neoplasms; Carotid Intima-Media Thickness; Cholesterol; Cyclic AMP-Dependent Protein Kinases; Drugs, Chinese Herbal; Estrogens; Female; Hep G2 Cells; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Lipid Metabolism; Lipids; Lipoproteins, LDL; MCF-7 Cells; Menopause; Models, Animal; Phosphorylation; Phytoestrogens; Rats; Rats, Sprague-Dawley

Calycosin and genistein are the two main components of isoflavones. Previously, we reported that these compounds display antitumor activities in the breast cancer cell lines MCF-7 and T47D. In the present study, we investigated the mechanism of action of calycosin and genistein, and their respective efficacies as potential therapies for the treatment of breast carcinoma in the clinic.. MCF-7 cells were treated with calycosin or genistein. Cell proliferation and apoptosis were measured using CCK8 assay and Hoechst 33258. The expression level of phosphorylated Akt protein was determined by western blotting. Expression level of HOTAIR was quantified by real-time PCR.. Both calycosin and genistein inhibited proliferation and induced apoptosis in MCF-7 breast cancer cells, especially after treatment with calycosin. Treatment of MCF-7 cells with calycosin or genistein resulted in decreased phosphorylation of Akt, and decreased expression of its downstream target, HOTAIR.. Calycosin is more effective in inhibiting breast cancer growth in comparison with genistein, through its regulation of Akt signaling pathways and HOTAIR expression.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Female; Genistein; Humans; Isoflavones; MCF-7 Cells; Phosphorylation; Phytoestrogens; Proto-Oncogene Proteins c-akt; RNA, Long Noncoding; Signal Transduction

Genistein is an estrogenic soy-derived compound belonging to the isoflavone class and shows anti-cancer effects. However, the specific cell apoptosis mechanisms of genistein have not been fully understood. In this study, we investigated the specific cell apoptosis mechanisms of genistein and the potential involvement of the IGF1R-Akt-Bcl-2 and Bax-mediated pathways in human breast cancer cells in vitro. MCF-7 human breast cancer cells were treated with various concentrations of genistein, and cell proliferation was evaluated by the MTT assay. Morphological changes in treated cells were examined by Hoechst 33258 staining, and treated cells were examined by flow cytometry. The levels of IGF-1R, p-Akt, Bcl-2, and Bax protein expression and Bcl-2 and Bax mRNA expression were evaluated by western blot and RT-PCR, respectively. Genistein inhibited the proliferation of MCF-7 cells and induced cell apoptosis, as determined by Hoechst staining and flow cytometry analysis. Furthermore, genistein induced the inactivation of IGF-1R and p-Akt and downregulated the Bcl-2/Bax protein ratio. These results suggest that genistein inhibited cell proliferation by inactivating the IGF-1R-PI3 K/Akt pathway and decreasing the Bcl-2/Bax mRNA and protein expressions. Our findings help elucidate the mechanisms by which genistein may contribute to the prevention of breast cancer carcinogenesis.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Genistein; Humans; MCF-7 Cells; Osmolar Concentration; Phosphorylation; Phytoestrogens; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Receptor, IGF Type 1; Receptors, Somatomedin; RNA, Messenger; Signal Transduction

Low bone mineral density (BMD) is common among breast cancer survivors due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens, namely isoflavones, known to have both estrogenic and anti-estrogenic effects. The objective of the study was to assess the association between soy consumption and BMD in breast cancer survivors, which has not previously been evaluated.. Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60 months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis were averaged, and the association with BMD, osteopenia, and osteoporosis was evaluated using linear and logistic regression.. The mean (standard deviation) intake of isoflavones was 48.1 (28.0) mg/day. Soy intake was inversely associated with BMD and positively associated with osteoporosis. Compared with the lowest quartile, the highest quartile of soy isoflavone intake, ≥ 62.64 mg/day, was associated with a reduction of BMD by 1.95% [95% confidence interval (CI) -3.54, -0.36%] and an increased odds ratio of 1.69 for osteoporosis (95% CI 1.09, 2.61). The inverse association was predominantly seen among women who recently entered menopause (≤ 5 years).. In contrast to observations from general populations, high soy intake (≥ 62.64 mg of soy isoflavone/day) was associated with lower proximal forearm BMD among breast cancer survivors, particularly during the early years of menopause. Our finding needs to be replicated, particularly in studies with more comprehensive bone density evaluation.

Topics: Absorptiometry, Photon; Adult; Aged; Bone Density; Breast Neoplasms; China; Female; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Prospective Studies; Soy Foods; Survivors

Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here.. Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen-receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival.. Our findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cluster Analysis; Computational Biology; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genistein; Humans; Isoflavones; MCF-7 Cells; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Ovariectomy; Phytoestrogens; Random Allocation; Soy Foods; Tumor Burden; Xenograft Model Antitumor Assays

Mango fruit contain many bioactive compounds, some of which are transcription factor regulators. Estrogen receptor alpha (ERα) and beta (ERβ) are two regulators of gene transcription that are important in a variety of physiological processes and also in diseases including breast cancer. We examined the ability of the mango constituents quercetin, mangiferin, and the aglycone form of mangiferin, norathyriol, to activate both isoforms of the estrogen receptor. Quercetin and norathyriol decreased the viability of MCF-7 breast cancer cells whereas mangiferin had no effect on MCF-7 cells. We also determined that quercetin and mangiferin selectively activated ERα whereas norathyriol activated both ERα and ERβ. Despite quercetin, mangiferin and norathyriol having similar polyphenolic structural motifs, only norathyriol activated ERβ, showing that bioactive agents in mangoes have very specific biological effects. Such specificity may be important given the often-opposing roles of ERα and ERβ in breast cancer proliferation and other cellular processes.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Survival; Chlorocebus aethiops; COS Cells; Estrogen Receptor alpha; Estrogen Receptor Antagonists; Estrogen Receptor beta; Female; Fruit; Genes, Reporter; Humans; Mangifera; MCF-7 Cells; Neoplasm Proteins; Phytoestrogens; Quercetin; Recombinant Proteins; Response Elements; Transcriptional Activation; Xanthenes; Xanthones

Breast cancer prevention efforts are focused increasingly on potentially beneficial dietary modifications due to their ease of implementation and wide acceptance. Secoisolariciresinol diglucoside (SDG) is a lignan found in high concentration in flaxseed that may have selective estrogen receptor modulator-like effects resulting in antiestrogenic activity in a high estrogen environment. In parallel with a human phase II prevention trial, female ACI rats (n = 8-10/group) received 0, 10, or 100 ppm SDG in the feed. The 100 ppm SDG treatment produced similar blood lignan levels as those observed in our human pilot study. Mammary and ovarian cancer progression were induced using local ovarian DMBA treatment and subcutaneous sustained release 17β-estradiol administered starting at 7 weeks of age. Mammary gland and ovarian tissues were collected at 3 mo after initiation of treatment and examined for changes in epithelial cell proliferation (Ki-67, cell counts), histopathology, and dysplasia scores, as well as expression of selected genes involved in proliferation, estrogen signaling, and cell adhesion. Treatment with SDG normalized several biomarkers in mammary gland tissue (dysplasia, cell number, and expression of several genes) that had been altered by carcinogen. There is no indication that SDG promotes preneoplastic progression in the ovarian epithelium.

Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Butylene Glycols; Cell Adhesion; Disease Models, Animal; Disease Progression; Drug Evaluation, Preclinical; Estrogen Receptor Modulators; Female; Flax; Glucosides; Ki-67 Antigen; Ovarian Neoplasms; Phytoestrogens; Precancerous Conditions; Rats; Rats, Inbred ACI; Seeds

Glycitein is an O-methylated isoflavone which accounts for 5-10% of the total isoflavones in soy food products. Cell proliferation studies on the dietary phytoestrogen, glycitein against human breast carcinoma SKBR-3 cells showed that glycitein exhibits biphasic regulation on SKBR-3 cells. At concentrations of less than 10 mg/mL, cells respond to glycitein by increasing cell growth and de novo DNA synthesis whereas the addition of glycitein at concentrations greater than 30 mg/mL significantly inhibited cell growth and DNA synthesis in a dose-dependent manner. Cells treated with 60 mg/mL of glycitein did not regain normal growth after treatment was stopped. Glycitein was found to be cytostatic at low concentrations and cytotoxic at higher concentrations. Treatment with 100 mg/mL of glycitein severely altered the cell morphology. Collective results showed that glycitein damaged the cell membranes by increasing membrane permeability and suggested possible mechanisms of the action of dietary phytoestrogens on human breast carcinoma SKBR-3 cells.

Topics: Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Genistein; Humans; Isoflavones; Phytoestrogens

BRF2 is a transcription factor required for synthesis of a small group of non-coding RNAs by RNA polymerase III. Overexpression of BRF2 can transform human mammary epithelial cells. In both breast and lung cancers, the BRF2 gene is amplified and overexpressed and may serve as an oncogenic driver. Furthermore, elevated BRF2 can be independently prognostic of unfavorable survival. Dietary soy isoflavones increase metastasis to lungs in a model of breast cancer and a recent study reported significantly increased cell proliferation in breast cancer patients who used soy supplementation. The soy isoflavone daidzein is a major food-derived phytoestrogen that is structurally similar to estrogen. The putative estrogenic effect of soy raises concern that high consumption of soy foods by breast cancer patients may increase tumor growth.. Expression of BRF2 RNA and protein was assayed in ER-positive or -negative human breast cancer cells after exposure to daidzein. We also measured mRNA stability, promoter methylation and response to the demethylating agent 5-azacytidine. In addition, expression was compared between mice fed diets enriched or deprived of isoflavones.. We demonstrate that the soy isoflavone daidzein specifically stimulates expression of BRF2 in ER-positive breast cancer cells, as well as the related factor BRF1. Induction is accompanied by increased levels of non-coding RNAs that are regulated by BRF2 and BRF1. Daidzein treatment stabilizes BRF2 and BRF1 mRNAs and selectively decreases methylation of the BRF2 promoter. Functional significance of demethylation is supported by induction of BRF2 by the methyltransferase inhibitor 5-azacytidine. None of these effects are observed in an ER-negative breast cancer line, when tested in parallel with ER-positive breast cancer cells. In vivo relevance is suggested by the significantly elevated levels of BRF2 mRNA detected in female mice fed a high-isoflavone commercial diet. In striking contrast, BRF2 and BRF1 mRNA levels are suppressed in matched male mice fed the same isoflavone-enriched diet.. The BRF2 gene that is implicated in cancer can be induced in human breast cancer cells by the isoflavone daidzein, through promoter demethylation and/or mRNA stabilization. Dietary isoflavones may also induce BRF2 in female mice, whereas the converse occurs in males.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; DNA Methylation; Female; Humans; Isoflavones; Male; Neoplasm Proteins; Phytoestrogens; Promoter Regions, Genetic; Proto-Oncogene Mas; RNA, Messenger; RNA, Neoplasm; TATA-Binding Protein Associated Factors; Transcription Factor TFIIIB

Estrogen replacement therapy is commonly used to replace the loss of estrogen in post-menopausal women. However, it is not suitable to be used in women taking tamoxifen as both of the drugs increase the risk of endometrial cancer. This project aimed to study the potential of using the natural compound glabridin in combination with tamoxifen as a drug for estrogen replacement therapy. Ishikawa and MCF-7 cells were used to investigate the estrogenic activities stimulated by the combination of tamoxifen and glabridin through ALP and MTT assays. The expressions of the ESR1 and bcl-2 genes have also been determined using RT-PCR. The results indicated that the combination of 1 x 10(-5)M tamoxifen and 1 x 10(-6)M glabridin exhibited estrogenic activities and suppressed cell growth in both cell lines. The relative expressions of ESR1 and bcl-2 genes indicated that the estrogenicity expressed by the combinatory drug was regulated by estrogen receptor a; however, the reduction in cell proliferation was not modulated by bcl-2 anti-apoptotic proteins. These results suggested that the combination of tamoxifen and glabridin has potential to be used as an estrogen replacement drug with a reduced risk of endometrial cancer that has arisen from the intake of tamoxifen.

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Drug Therapy, Combination; Endometrial Neoplasms; Estrogens; Female; Humans; Isoflavones; Phenols; Phytoestrogens; Selective Estrogen Receptor Modulators; Tamoxifen

Plants of the genus Taraxacum, commonly known as dandelions, are used to treat breast cancer in traditional folk medicine. However, their use has mainly been based on empirical findings without sufficient scientific evidence. Therefore, we hypothesized that dandelions would behave as a Selective estrogen receptor modulator (SERM) and be effective as hormone replacement therapy (HRT) in the postmenopausal women. In the present study, in vitro assay systems, including cell proliferation assay, reporter gene assay, and RT-PCR to evaluate the mRNA expression of estrogen-related genes (pS2 and progesterone receptor, PR), were performed in human breast cancer cells. Dandelion ethanol extract (DEE) significantly increased cell proliferation and estrogen response element (ERE)-driven luciferase activity. DEE significantly induced the expression of estrogen related genes such as pS2 and PR, which was inhibited by tamoxifen at 1 μmol·L(-1). These results indicated that DEE could induce estrogenic activities mediated by a classical estrogen receptor pathway. In addition, immature rat uterotrophic assay was carried out to identify estrogenic activity of DEE in vivo. The lowest concentration of DEE slightly increased the uterine wet weight, but there was no significant effect with the highest concentration of DEE. The results demonstrate the potential estrogenic activities of DEE, providing scientific evidence supporting their use in traditional medicine.

Topics: Animals; Breast Neoplasms; Cell Proliferation; Estrogen Replacement Therapy; Female; Gene Expression; Humans; MCF-7 Cells; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Leaves; Rats; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Taraxacum; Uterus

To explore the effect and pathway of phytoestrogens on the growth of breast cancer cell line MCF-7.. MCF-7 cells (human estrogen receptor-positive and progesterone receptor-positive breast cancer cells) were cultured in serum-free medium for 24 h and then treated with genistein, resveratrol, and quercetin (10(-10)-10(-4) mol/l). After further incubation for 24, 48, 72, and 92 h, the cells were harvested and extracted for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. According to the above results, the proteins involving proliferative and apoptotic pathways were evaluated by Western blot analysis.. Genistein, resveratrol, and quercetin significantly inhibited cellular proliferation in a dose- and time-dependent manner. Significantly elevated caspase-3 activity was noted after treatment with genistein (10(-9)-10(-7) mol/l), as well as with resveratrol and quercetin (10(-9)-10(-5) mol/l). Significant reduction of PI3K and AKT protein and significant increase of Fas ligand, Fas-associated protein with death domain, cytochrome C, truncated Bid, caspase-9, and caspase-3 were all noted after genistein, resveratrol, and quercetin treatment. 17β-Estradiol induced completely opposite results. Estrogen receptor (ER) α expression was significantly increased with 17β-estradiol, whereas ERβ expression was significantly elevated in the cultures with genistein, resveratrol, and quercetin.. These data demonstrate that genistein, resveratrol, and quercetin have antiproliferative effects on breast cancer cells. Their induction of apoptosis involves the activation of both the intrinsic and extrinsic apoptotic pathways, which may be related to the differential affinity to ERα and ERβ. Whether phytoestrogens have similar effects on normal breast cells remains to be examined.

Topics: Apoptosis; Breast Neoplasms; Caspase 3; Cell Proliferation; Estradiol; Fas Ligand Protein; Female; Genistein; Humans; MCF-7 Cells; Mitochondria; Phosphatidylinositol 3-Kinases; Phytoestrogens; Proto-Oncogene Proteins c-akt; Quercetin; Resveratrol; Signal Transduction; Stilbenes

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERβ and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

Topics: Animals; Breast Neoplasms; Endocrine Disruptors; Humans; Phytoestrogens; Receptors, Estrogen; Risk Factors; Signal Transduction

Soy foods are the richest sources of isoflavones, mainly daidzein and genistein. Soy isoflavones are structurally similar to the steroid hormone 17β-estradiol and may protect against breast cancer. S-(-)equol, a metabolite of the soy isoflavone daidzein, has a higher bioavailability and greater affinity for estrogen receptor β than daidzein. Approximately one-third of the Western population is able to produce S-(-)equol, and the ability is linked to certain gut microbes. We hypothesized that the prevalence of breast cancer, ductal hyperplasia, and overall breast pathology will be lower among S-(-)equol producing, as compared with nonproducing, postmenopausal women undergoing a breast biopsy. We tested our hypothesis using a cross-sectional study design. Usual diets of the participants were supplemented with 1 soy bar per day for 3 consecutive days. Liquid chromatography-multiple reaction ion monitoring mass spectrometry analysis of urine from 143 subjects revealed 25 (17.5%) as S-(-)equol producers. We found no statistically significant associations between S-(-)equol producing status and overall breast pathology (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.23-1.89), ductal hyperplasia (OR, 0.84; 95% CI, 0.20-3.41), or breast cancer (OR, 0.56; 95% CI, 0.16-1.87). However, the mean dietary isoflavone intake was much lower (0.3 mg/d) than in previous reports. Given that the amount of S-(-)equol produced in the gut depends on the amount of daidzein exposure, the low soy intake coupled with lower prevalence of S-(-)equol producing status in the study population favors toward null associations. Findings from our study could be used for further investigations on S-(-)equol producing status and disease risk.

Topics: Aged; Biological Availability; Biopsy; Breast; Breast Neoplasms; Cross-Sectional Studies; Diet; Dietary Supplements; Equol; Estrogen Receptor beta; Feeding Behavior; Female; Glycine max; Humans; Isoflavones; Middle Aged; Odds Ratio; Phytoestrogens; Postmenopause; Soy Foods; United States

Several plant-derived molecules, referred to as phytoestrogens, are thought to mimic the actions of endogenous estrogens. Among these, quercetin, one of the most widespread flavonoids in the plant kingdom, has been reported as estrogenic in some occasions. However, quercetin occurs in substantial amounts as glycosides such as quercetin-3-O-glucoside (isoquercitrin) and quercetin-3-O-rutinoside (rutin) in dietary sources. It is now well established that quercetin undergoes substantial phase II metabolism after ingestion by humans, with plasma metabolites after a normal dietary intake rarely exceeding nmol/L concentrations. Therefore, attributing phytoestrogenic activity to flavonoids without taking into account the fact that it is their phase II metabolites that enter the circulatory system, will almost certainly lead to misleading conclusions. With the aim of clarifying the above issue, the goal of the present study was to determine if plant-associated quercetin glycosides and human phase II quercetin metabolites, actually found in human biological fluids after intake of quercetin containing foods, are capable of interacting with the estrogen receptors (ER). To this end, we used a yeast-based two-hybrid system and an estrogen response element-luciferase reporter assay in an ER-positive human cell line (MCF-7) to probe the ER interaction capacities of quercetin and its derivatives. Our results show that quercetin-3-O-glucuronide, one of the main human phase II metabolites produced after intake of dietary quercetin, displays ERα- and ERβ-dependent estrogenic activity, the functional consequences of which might be related to the protective activity of diets rich in quercetin glycosides.

Topics: Breast Neoplasms; Glucuronides; Humans; MCF-7 Cells; Phytoestrogens; Quercetin; Saccharomyces cerevisiae

Phytoestrogens have been investigated as natural alternatives to hormone replacement therapy and their potential as chemopreventive agents. We investigated the effects of equol, genistein, and coumestrol on cell growth in fully estrogenized MCF7 cells, simulating the perimenopausal state, and long-term estrogen-deprived MCF7:5C cells, which simulate the postmenopausal state of a woman after years of estrogen deprivation, and compared the effects with that of steroidal estrogens: 17β estradiol (E2) and equilin present in conjugated equine estrogen. Steroidal and phytoestrogens induce proliferation of MCF7 cells at physiologic concentrations but inhibit the growth and induce apoptosis of MCF7:5C cells. Although steroidal and phytoestrogens induce estrogen-responsive genes, their antiproliferative and apoptotic effects are mediated through the estrogen receptor. Knockdown of ERα using siRNA blocks all estrogen-induced apoptosis and growth inhibition. Phytoestrogens induce endoplasmic reticulum stress and inflammatory response stress-related genes in a comparable manner as the steroidal estrogens. Inhibition of inflammation using dexamethasone blocked both steroidal- and phytoestrogen-induced apoptosis and growth inhibition as well as their ability to induce apoptotic genes. Together, this suggests that phytoestrogens can potentially be used as chemopreventive agents in older postmenopausal women but caution should be exercised when used in conjunction with steroidal anti-inflammatory agents due to their antiapoptotic effects.

Topics: Apoptosis; Breast Neoplasms; Estrogens; Humans; Immunoblotting; In Vitro Techniques; MCF-7 Cells; Phytoestrogens; Postmenopause; Real-Time Polymerase Chain Reaction; RNA, Small Interfering; Transfection

Over the past 2 decades, soy foods have been the subject of a vast amount of research, primarily because they are uniquely rich sources of isoflavones. Isoflavones are classified as both phytoestrogens and selective estrogen receptor modulators. The phytoestrogenic effects of isoflavones have led some to view soy foods and isoflavone supplements as alternatives to conventional hormone therapy. However, clinical research shows that isoflavones and estrogen exert differing effects on a variety of health outcomes. Nevertheless, there is substantial evidence that soy foods have the potential to address several conditions and diseases associated with the menopausal transition. For example, data suggest that soy foods can potentially reduce ischemic heart disease through multiple mechanisms. Soy protein directly lowers blood low-density lipoprotein-cholesterol concentrations, and the soybean is low in saturated fat and a source of both essential fatty acids, the omega-6 fatty acid linoleic acid and the omega-3 fatty acid alpha-linolenic acid. In addition, soflavones improve endothelial function and possibly slow the progression of subclinical atherosclerosis. Isoflavone supplements also consistently alleviate menopausal hot flashes provided they contain sufficient amounts of the predominant soybean isoflavone genistein. In contrast, the evidence that isoflavones reduce bone loss in postmenopausal women is unimpressive. Whether adult soy food intake reduces breast cancer risk is unclear. Considerable evidence suggests that for soy to reduce risk, consumption during childhood and/or adolescence is required. Although concerns have been raised that soy food consumption may be harmful to breast cancer patients, an analysis in 9514 breast cancer survivors who were followed for 7.4 y found that higher postdiagnosis soy intake was associated with a significant 25% reduction in tumor recurrence. In summary, the clinical and epidemiologic data indicate that adding soy foods to the diet can contribute to the health of postmenopausal women.

Topics: Breast Neoplasms; Cardiovascular Diseases; Diet; Fatty Acids, Unsaturated; Female; Glycine max; Health; Hot Flashes; Humans; Isoflavones; Phytoestrogens; Postmenopause; Soy Foods; Soybean Proteins

To explore the effect and pathway of phytoestrogens in vitro on the growth of both normal and malignant breast cells.. Normal breast MCF-10A cells and breast cancer MCF-7 cells were incubated with 10 (-10)-10(-4)  mol/l genistein, resveratrol, and quercetin (plasma concentrations in human: 10 nmol/l-10 μmol/l) for 48 h and were then extracted for a cell proliferation assay (MTT), and for a cell death assay (TUNEL) assay. The proteins involved in the proliferative and apoptotic pathways were evaluated by Western blot analysis. Additionally, a comparison with 17β-estradiol as well as an evaluation of the differential effects on estrogen receptors (ER) α and β were performed.. MCF-7 cell proliferation was significantly inhibited at the concentrations greater than 10(-4) mol/l for all three phytoestrogens and from 10 (-5) mol/l for resveratrol and quercetin. MCF-10A cell proliferation was significantly increased at the concentrations from 10 (-8) to 10 (-5) mol/l for genistein and resveratrol and only at 10 (-5) mol/l for quercetin. Apoptotic cells were significantly increased by these phytoestrogens in the MCF-7 cells. At a concentration of 10 (-7)  mol/l of these phytoestrogens, a significant reduction of PI3K and Akt and an increase of Fas ligand, Fas-associated protein with death domain, cytochrome C, truncated Bid, caspase-9, and caspase-3 were noted in the MCF-7; PI3K and Akt were significantly increased in the MCF-10A. ERβ expression was significantly elevated in MCF-10A and MCF-7 with these phytoestrogens. The effects of estradiol on normal and malignant breast cells were completely opposite to those of phytoestrogens.. This study demonstrates that phytoestrogens have antiproliferative effects on breast cancer cells via an ER-dependent mechanism, even at low concentrations, but are also capable of maintaining the survival of normal breast cell via ER-independent or other mechanisms.

Topics: Apoptosis; Breast; Breast Neoplasms; Cell Line; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genistein; Humans; In Situ Nick-End Labeling; MCF-7 Cells; Phytoestrogens; Quercetin; Resveratrol; Signal Transduction; Stilbenes

Hops (Humulus lupulus L.) produce unique prenylflavonoids that exhibit interesting bioactivities. This study investigates the interactions between selected prenylflavonoids and breast cancer resistance protein (BCRP/ABCG2), an efflux transporter important for xenobiotic bioavailability and multidrug resistance (MDR).. ABCG2-inhibitory activity of xanthohumol (XN), isoxanthohumol (IX), 6-prenylnaringenin (6-PN), 8-prenylnaringenin (8-PN), and 6,8-diprenylnarigenin (6,8-diPN) was evaluated using mitoxantrone accumulation and vesicular transport assays. XN, IX, and 8-PN were tested for a substrate-type relationship with ABCG2 using ATPase and bidirectional transport assays. The prenylflavonoids exhibited significant ABCG2-inhibitory activities in mitoxantrone accumulation and vesicular transport assays. In the ATPase assay, XN, IX, and 8-PN inhibited baseline and sulfasalazine-stimulated ATPase activities with IC50 of 2.16-27.0 μM. IX and 8-PNalso displayed bell-shaped activation curves in Ko143-suppressed membranes, indicating a substrate-type relationship. For IX, efflux ratios of 1.25 ± 0.21 and 9.18 ± 0.56 were observed in wild type and ABCG2-overexpressing MDCKII cell monolayers, respectively. The latter was reduced to 1.25 ± 0.15 in the presence of the ABCG2-specific inhibitor Ko143, demonstrating an ABCG2-mediated efflux of IX. Additionally, evidence was shown for the involvement of ABCG2 in the efflux of 8-PN and/or its sulfate conjugate.. Prenylflavonoids are potent inhibitors of ABCG2 and therefore implicated in ABCG2-mediated food/herb-drug interactions and MDR. ABCG2-mediated efflux of prenylflavonoids may represent one mechanism that regulates prenylflavonoid bioavailability.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Availability; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Flavanones; Flavonoids; Gene Expression Regulation, Neoplastic; HEK293 Cells; Herb-Drug Interactions; Humans; Humulus; Membrane Transport Proteins; Mitoxantrone; Neoplasm Proteins; Phytoestrogens; Propiophenones; Xanthones; Xenobiotics

The isoflavones genistein, daidzein and equol (daidzein metabolite) have been reported to interact with epigenetic modifications, specifically hypermethylation of tumor suppressor genes. The objective of this study was to analyze and understand the mechanisms by which phytoestrogens act on chromatin in breast cancer cell lines.. Two breast cancer cell lines, MCF-7 and MDA-MB 231, were treated with genistein (18.5 µM), daidzein (78.5 µM), equol (12.8 µM), 17β-estradiol (10 nM) and suberoylanilide hydroxamic acid (1 µM) for 48 h. A control with untreated cells was performed. 17β-estradiol and an anti-HDAC were used to compare their actions with phytoestrogens. The chromatin immunoprecipitation coupled with quantitative PCR was used to follow soy phytoestrogen effects on H3 and H4 histones on H3K27me3, H3K9me3, H3K4me3, H4K8ac and H3K4ac marks, and we selected six genes (EZH2, BRCA1, ERα, ERβ, SRC3 and P300) for analysis.. Soy phytoestrogens induced a decrease in trimethylated marks and an increase in acetylating marks studied at six selected genes.. We demonstrated that soy phytoestrogens tend to modify transcription through the demethylation and acetylation of histones in breast cancer cell lines.

Topics: Acetylation; Breast Neoplasms; Chromatin; DNA Methylation; Epigenesis, Genetic; Estrogens; Female; Gene Expression Regulation, Neoplastic; Glycine max; Histone Deacetylase Inhibitors; Histone Demethylases; Histones; Humans; Lysine; MCF-7 Cells; Phytoestrogens

Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied in vitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulphate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives.. Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human oestrogen receptors α and β and the human coactivator Tif2, we have systematically examined the oestrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3-O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3-O-sulphate, trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide). Only resveratrol-3-O-sulphate was found to display a fairly strong and oestrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an oestrogen-responsive promoter.. We show, for the first time, that resveratrol-3-O-sulphate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Binding Sites; Breast Neoplasms; Cell Line, Tumor; Clone Cells; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Glucosides; Glucuronides; Humans; MCF-7 Cells; Neoplasm Proteins; Nuclear Receptor Coactivator 2; Peptide Fragments; Phytoestrogens; Recombinant Proteins; Resveratrol; Stereoisomerism; Stilbenes; Sulfates

The relative importance of biochemical pathways has not been previously examined when considering the influence of diet on breast cancer risk. To address this issue, we used interview data from a population-based sample of 1463 breast cancer cases and 1500 controls. Dietary intake was assessed shortly after diagnosis using a 101-item food frequency questionnaire. Age- and energy-adjusted odds ratios (ORs) for individual micro- and macronutrients were estimated with logistic regression. Hierarchical modeling was used to account for biologically plausible nutrient pathways (1-carbon metabolism, oxidative stress, glycemic control, and phytoestrogens). Effect estimates from hierarchical modeling were more precise and plausible compared to those from multivariable models. The strongest relationship observed was for the glycemic control pathway, but confidence intervals (CI) were wide [OR (95% CI): 0.86 (0.62, 1.21)]. Little or no effect was observed for the 1-carbon metabolism, oxidative stress, and phytoestrogen pathways. Associations were similar when stratified by supplement use. Our approach that emphasizes biochemical pathways, rather than individual nutrients, revealed that breast cancer risk may be more strongly associated with glycemic control factors than those from other pathways considered. Our study emphasizes the importance of accounting for multiple nutrient pathways when examining associations between dietary intake and breast cancer.

Topics: Aged; Blood Glucose; Breast Neoplasms; Diet; Dietary Carbohydrates; Dietary Supplements; Female; Folic Acid; Humans; Logistic Models; Micronutrients; Middle Aged; New York; Odds Ratio; Oxidative Stress; Phytoestrogens; Risk Factors; Surveys and Questionnaires

Breast cancer treatment by the aromatase inhibitor Letrozole (LET) or Selective Estrogen Receptor Modulator Tamoxifen (TAM) can result in the onset of menopausal symptoms. Women often try to relieve these symptoms by taking menopausal supplements containing high levels of phytoestrogens. However, little is known about the potential interaction between these supplements and breast cancer treatment, especially aromatase inhibitors. In this study, interaction of phytoestrogens with the estrogen receptor alpha and TAM action was determined in an ER-reporter gene assay (BG1Luc4E2 cells) and human breast epithelial tumor cells (MCF-7). Potential interactions with aromatase activity and LET were determined in human adrenocorticocarcinoma H295R cells. We also used the previously described H295R/MCF-7 co-culture model to study interactions with steroidogenesis and tumor cell proliferation. In this model, genistein (GEN), 8-prenylnaringenin (8PN) and four commercially available menopausal supplements all induced ER-dependent tumor cell proliferation, which could not be prevented by physiologically relevant LET and 4OH-TAM concentrations. Differences in relative effect potencies between the H295R/MCF-7 co-culture model and ER-activation in BG1Luc4E2 cells, were due to the effects of the phytoestrogens on steroidogenesis. All tested supplements and GEN induced aromatase activity, while 8PN was a strong aromatase inhibitor. Steroidogenic profiles upon GEN and 8PN exposure indicated a strong inhibitory effect on steroidogenesis in H295R cells and H295R/MCF-7 co-cultures. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dietary Supplements; Dose-Response Relationship, Drug; Drug Antagonism; Female; Gene Expression Regulation, Neoplastic; Humans; Menopause; Phytoestrogens; Receptors, Estrogen

Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for antitumor effects remains unknown. Herein, we report that post-weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein (GEN) lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain GEN's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated GEN's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation into adipocytes. MSF cells cultured in a differentiation medium with 40 nM GEN showed reductions in mature adipocyte numbers, triglyceride accumulation, and Pparγ (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor β (Erβ (Esr2)) gene expression and was modestly recapitulated by ERβ-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Erβ expression by siRNA targeting increased Pparγ transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by GEN but not by DPN. Conditioned medium from GEN-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation of mammary adiposity by GEN for breast cancer prevention.

Topics: Adipogenesis; Adiposity; Animals; Anticarcinogenic Agents; Breast Neoplasms; Cadherins; Cell Adhesion; Female; Gene Expression Regulation, Neoplastic; Genistein; Humans; Lipid Metabolism; Mammary Glands, Human; MCF-7 Cells; Mice; Mice, Inbred Strains; Phytoestrogens; Plant Proteins, Dietary; PTEN Phosphohydrolase; RNA, Messenger; Soybean Proteins; Weaning

DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed.

Topics: Adult; Age Factors; Breast Feeding; Breast Neoplasms; Diet Surveys; Dietary Supplements; Female; Humans; Isoflavones; Lignans; Menarche; Middle Aged; Parity; Phytoestrogens; Plant Extracts; Prognosis; Prospective Studies; Recurrence; Smoking; Surveys and Questionnaires; Survivors; United Kingdom

Phytoestrogens have a controversial effect on hormone-dependent tumours. Herein, we investigated the effect of the pumpkin seed extract (PSE) on estradiol production and estrogen receptor (ER)-α/ER-β/progesterone receptor (PR) status on MCF7, Jeg3, and BeWo cells. The PSE was prepared and analyzed by mass spectrometry. MCF7, Jeg3, and BeWo cells were incubated with various concentrations of PSE. Untreated cells served as controls. Supernatants were tested for estradiol production with an ELISA method. Furthermore, the effect of the PSE on ER-α/ER-β/PR expression was assessed by immunocytochemistry. The PSE was found to contain both lignans and flavones. Estradiol production was elevated in MCF7, BeWo, and Jeg3 cells in a concentration-dependent manner. In MCF7 cells, a significant ER-α downregulation and a significant PR upregulation were observed. The above results after properly designed animal studies could highlight a potential role of pumpkin seed's lignans in breast cancer prevention and/or treatment.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cucurbita; Down-Regulation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Flavones; Humans; Immunohistochemistry; Lignans; MCF-7 Cells; Phytoestrogens; Plant Extracts; Receptors, Progesterone; Seeds; Trophoblastic Neoplasms; Up-Regulation

Adjuvant hormonal therapy using tamoxifen or aromatase inhibitors result in menopausal symptoms. Non-prescription dietary supplements containing plant-based phytoestrogens are often used to relieve menopausal symptoms. Phytoestrogens may reduce the action of tamoxifen and aromatase inhibitors. The purpose of this study is to gain insight into the potential risks of phytoestrogen supplementation during adjuvant hormonal therapy for breast cancer using tamoxifen or aromatase inhibitors.. Literature survey.. We performed a PubMed search for articles about studies on the effects of phytoestrogens on breast cancer treatment efficacy. We also searched on the basis of references in the articles we found in PubMed.. Studies based on in-vitro models as well as experimental animal models were identified. The studies on the interaction between phytoestrogen and tamoxifen showed contradictory results. The few studies pertaining to the interactive effect of phytoestrogens on aromatase inhibitors all showed a reduction in therapeutic efficacy of aromatase inhibitors caused by phytoestrogens.. The outcomes of the studies we found suggest that caution should be exercised when taking phytoestrogen in combination with either tamoxifen or aromatase inhibitors. We believe that patients with breast cancer should be informed of this as a matter of routine.

Topics: Aromatase Inhibitors; Breast Neoplasms; Dietary Supplements; Drug Interactions; Female; Humans; Menopause; Phytoestrogens; Tamoxifen; Treatment Outcome

Phytoestrogen intake may reduce breast cancer risk and limited evidence suggests this association may hold for hormone receptor-positive tumors only. The study aims were to assess whether the association between phytoestrogen intake during adolescence and adulthood and breast cancer risk varies by estrogen and progesterone receptor (ERPR) tumor subgroup. Cases were identified from the Ontario Cancer Registry (2002-2003), and ERPR status was ascertained from pathology reports for 81% of cases (n = 2,438). Controls were identified through random digit dialing of Ontario households (n = 3,370). Published phytoestrogen food values were applied to food frequency questionnaire responses to assess isoflavone, lignan and total phytoestrogen intake, during adolescence and adulthood. Polytomous multivariate logistic regression was used to estimate adjusted odds ratios (ORs) for association between phytoestrogen intake and breast cancer risk by hormone receptor ERPR tumor subgroups. Among premenopausal women, few associations were observed for adolescent or adult phytoestrogen intake across all tumor subgroups. Among postmenopausal women, adolescent phytoestrogen intake (isoflavone, lignan and total) was associated with reduced risk across all hormone receptor subgroups; however, statistical significance was most consistent within the ER+PR+ subgroup. For example, ER+PR+ postmenopausal breast cancer risk was associated with adolescent phytoestrogen intake (highest vs. lowest: OR = 0.79; 95% confidence interval: 0.65-0.96). Among all women and postmenopausal women, ORs for high adult lignan intake were all below 1.0 within each tumor subgroup, suggesting reduced breast cancer risk, although none reached statistical significance. In conclusion, adolescent phytoestrogen intake was associated with reduced postmenopausal breast cancer, particularly for ER+PR+ tumor subgroup.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Case-Control Studies; Female; Humans; Incidence; Middle Aged; Odds Ratio; Ontario; Phytoestrogens; Postmenopause; Premenopause; Prognosis; Prospective Studies; Receptors, Estrogen; Receptors, Progesterone; Risk Factors; Surveys and Questionnaires

The scientific literature contains evidence suggesting that women who have been treated for breast cancer may, as a result of their diagnosis, increase their phyto-oestrogen (PE) intake. In the present paper, we describe the creation of a dietary analysis database (based on Dietplan6) for the determination of dietary intakes of specific PE (daidzein, genistein, glycitein, formononetin, biochanin A, coumestrol, matairesinol and secoisolariciresinol), in a group of women previously diagnosed and treated for postmenopausal breast cancer. The design of the database, data evaluation criteria, literature data entry for 551 foods and primary analysis by LC–MS/MS of an additional thirty-four foods for which there were no published data are described. The dietary intake of 316 women previously treated for postmenopausal breast cancer informed the identification of potential food and beverage sources of PE and the bespoke dietary analysis database was created to, ultimately, quantify their PE intake. In order that PE exposure could be comprehensively described, fifty-four of the 316 subjects completed a 24 h urine collection, and their urinary excretion results allowed for the description of exposure to include those identified as ‘equol producers’.

Topics: Aged; Breast Neoplasms; Databases as Topic; Diet Records; Equol; Female; Food Analysis; Humans; Isoflavones; Middle Aged; Phytoestrogens; Postmenopause; Statistics, Nonparametric

Si-Wu-Tang (SWT), comprising the combination of four herbs, Paeoniae, Angelicae, Chuanxiong and Rehmanniae, is one of the most popular traditional oriental medicines for women's diseases. In our previous study, the microarray gene expression profiles of SWT on breast cancer cell line MCF-7 were found similar to the effect of β-estradiol (E2) on MCF-7 cells in the Connectivity Map database.. Further data analysis was conducted to find the main similarities and differences between the effects of SWT and E2 on MCF-7 gene expression. The cell proliferation assay on MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) cells were used to examine such estrogenic activity. The estrogenic potency of SWT was further confirmed by estrogen-responsive element (ERE) luciferase reporter assay in MCF-7 cells.. Many estrogen regulated genes strongly up-regulated by E2 were similarly up-regulated by SWT, e.g., GREB1, PGR and EGR3. Of interest with regard to safety of SWT, the oncogenes MYBL1 and RET were strongly induced by E2 but not by SWT. Quantitative RT-PCR analysis revealed a highly concordant expression change in selected genes with data obtained by microarrays. Further supporting SWT's estrogenic activity, in MCF-7 but not in MDA-MB-231 cells, SWT stimulated cell growth at lower concentrations (< 3.0 mg/ml), while at high concentrations, it inhibits the growth of both cell lines. The growth inhibitory potency of SWT was significantly higher in MDA-MB-231 than in MCF-7 cells. The SWT-induced cell growth of MCF-7 could be blocked by addition of the estrogen receptor antagonist tamoxifen. In addition, SWT was able to activate the ERE activity at lower concentrations. The herbal components Angelicae, Chuanxiong and Rehmanniae at lower concentrations (< 3.0 mg/ml) also showed growth-inducing and ERE-activating activity in MCF-7 cells.. These results revealed a new mechanism to support the clinical use of SWT for estrogen related diseases and possibly for cancer prevention. This study also demonstrated the feasibility of using microarray transcriptional profiling to discover phytoestrogenic components that are present in natural products.

Topics: Breast Neoplasms; Cell Line, Tumor; Drugs, Chinese Herbal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Phytoestrogens; Transcription, Genetic

Phytoestrogens are plant-derived, non-steroidal phytochemicals with anticarcinogenic potential. The major structural classes are the isoflavones and lignans. The aim of this study was to compare the effect of the plant-derived lignans secoisolariciresinol and matairesinol with the human lignans enterodiol and enterolactone as well as with 17β estradiol and tamoxifen on cell proliferation of breast carcinoma cell lines.. The influence of the lignans, 17β estradiol and tamoxifen on cell proliferation was determined using the BrdU test in MCF 7 and BT 20 cell lines.. Enterodiol and enterolactone induced a stronger inhibition of cell growth in MCF 7 and BT 20 cells than secoisolariciresinol and matairesinol. The inhibition effects were less expressed in the BT 20 than in the MCF 7 cells.. The human lignans enterodiol and enterolactone are more biologically active than their precursors secoisolariciresinol and matairesinol, and may be defined as the real drugs in cancer prevention.

Topics: 4-Butyrolactone; Anticarcinogenic Agents; Breast Neoplasms; Butylene Glycols; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogens; Female; Furans; Humans; Lignans; Phytoestrogens; Selective Estrogen Receptor Modulators; Tamoxifen

S-Equol is a metabolite resulting from the conversion of daidzein, a soya phyto-oestrogen, by the gut microflora. The potential protective effects of equol in breast cancer are still under debate. Consequently, we investigated the effects of equol on DNA methylation of breast cancer susceptibility genes (BRCA1 and BRCA2) and oncosuppressors in breast cancer cell lines (MDA-MB-231 and MCF-7) and in a dystrophic breast cell line (MCF-10a) following exposure to S-equol (2 μm) for 3 weeks. We demonstrated by quantitative analysis of methylated alleles a significant decrease in the methylation of the cytosine phosphate guanine (CpG) islands in the promoters of BRCA1 and BRCA2 after the S-equol treatment in MCF-7 and MDA-MB-231 cells and a trend in MCF-10a cells. We also showed that S-equol increases BRCA1 and BRCA2 protein expression in the nuclei and the cytoplasm in MCF-7, MDA-MB-231 and MCF-10a cell lines by immunohistochemistry. The increase in BRCA1 and BRCA2 proteins was also found after Western blotting in the studied cell lines. In summary, we demonstrated the demethylating effect of S-equol on the CpG islands inside the promoters of BRCA1 and BRCA2 genes, resulting in an increase in the level of expressed oncosuppressors in breast cancer cell lines.

Topics: Alleles; Antineoplastic Agents, Phytogenic; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Cell Line, Tumor; Cell Nucleus; CpG Islands; Cytoplasm; DNA Methylation; Epigenesis, Genetic; Equol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Phytoestrogens; Promoter Regions, Genetic; Protein Transport; Up-Regulation

Intake of dietary phyto-oestrogens has received a great deal of attention owing to their potential influence on hormone-sensitive cancers such as breast and prostate cancer. Cows' milk contains phyto-oestrogens and the content varies according to the composition of the feed and the type and amount of legumes used. In this study we evaluated the proliferative effect of milk (whey) with different phyto-oestrogen content in human breast (MCF-7) and prostate cancer cells (PC-3). Milk was obtained from cows fed either a birdsfoot trefoil-timothy silage based ration (B1) or two different red clover silage based diets (R1 and R2) resulting in total phyto-oestrogen contents of 403, 1659 and 1434 ng/ml for the B1, R1 and R2 diets, respectively. Whey was produced from the milk and added to cell culture medium in concentrations up to 10% for MCF-7 cells and 5% for PC-3 cells. Cell proliferation was measured fluorometrically after 7 d for MCF-7 cells and 5 d for PC-3 cells. There was no significant difference in the proliferative effect of whey from the different dietary treatments at any of the whey concentrations tested. An anti-proliferative effect (P<0·01) of 5 and 10% whey was seen when tested in the presence of 10 pM oestradiol in the medium. This effect was independent of dietary treatment of cows. Whey induced a significant (P<0·01) proliferative response in PC-3 cells independent of dietary treatment. Purified equol in concentrations similar to equol concentrations in milk decreased PC-3 cell proliferation, and therefore the stimulatory effect of whey in PC-3 cells is believed to be mediated by other bioactives than equol. In conclusion, our results suggest that using whey in these proliferation assays, it was not possible to discriminate between milk with high or low levels of phyto-oestrogens.

Topics: Animal Feed; Animals; Breast Neoplasms; Cattle; Cell Line, Tumor; Cell Proliferation; Fabaceae; Female; Humans; Lotus; Male; Milk; Phleum; Phytoestrogens; Prostatic Neoplasms; Silage; Trifolium

Although soy phytoestrogens have been postulated to exert a protective effect against breast cancer, the attendant mechanisms, in particular epigenetics underpinnings, have remained elusive. We investigated the putative effects on DNA methylation by two naturally occurring isoflavones, genistein and daidzein, in a study of the BRCA1 and BRCA2 oncosuppressor genes in breast cancer cell lines (MCF-7, MDA-MB 231, and MCF10a). A demethylant agent, the 5-azacytidine, and a methylant, the budesonide, were used as treatment controls. DNA methylation of BRCA1 and BRCA2 was investigated with methylated DNA immunoprecipitation coupled with PCR. In parallel, protein expression was determined by Western blot, immunohistochemistry, and confocal microscopy. Our results suggest that treatment with 18.5 μM Genistein or 78.5 μM Daidzein might reverse DNA hypermethylation and restore the expression of the oncosuppressor genes BRCA1 and BRCA2. 5-Azacitydine also enhanced the reexpression of these genes while budesonide had an opposite effect. To the best of our knowledge, these observations, while requiring replication, provide new evidence on potential epigenetic mechanisms by which genistein and daidzein might contribute to regulation of the BRCA1 and BRCA2. Future studies are warranted on whether the demethylating effect of genistein and daidzein is global or focused on select candidate genes.

Topics: BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Budesonide; Cell Line, Tumor; DNA Methylation; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Genistein; Glycine max; Humans; Immunohistochemistry; Isoflavones; Phytoestrogens

Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERβ, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERβ is anti-proliferative. Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers. Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/β heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/β heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays, we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Growth Inhibitors; Humans; Ligands; Male; Phytoestrogens; Prostatic Neoplasms; Protein Multimerization; Receptors, Estrogen

Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are still unknown. This study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of sub G(0)/G(1) apoptotic fractions. Overexpression of HER2 did not confer resistance to apigenin in MCF-7 cells. Apigenin-induced extrinsic apoptosis pathway up-regulating the levels of cleaved caspase-8, and inducing the cleavage of poly (ADP-ribose) polymerase, whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B-cell lymphoma 2 (BCL2) and Bcl-2-associated X protein. Moreover, apigenin reduced the tyrosine phosphorylation of HER2 (phospho-HER2 level) in MCF-7 HER2 cells, and up-regulated the levels of p53, phospho-p53 and p21 in MCF-7 vec and MCF-7 HER2 cells. This suggests that apigenin induces apoptosis through p53-dependent pathway. Apigenin also reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in MCF-7 vec and MCF-7 HER2 cells. Apigenin decreased the phosphorylation level of IκBα in the cytosol, and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF-7 vec and MCF-7 HER2 cells. Our study indicates that apigenin could be a potential useful compound to prevent or treat HER2-overexpressing breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins; Membrane Potential, Mitochondrial; NF-kappa B; Phytoestrogens; Receptor, ErbB-2; Signal Transduction; STAT3 Transcription Factor; Tumor Suppressor Protein p53

Phytoestrogens are structurally similar to estrogens and may affect breast cancer risk by mimicking estrogenic/antiestrogenic properties. In Western societies, whole grains and possibly soy foods are rich sources of phytoestrogens. A population-based case-control study in German postmenopausal women was used to evaluate the association of phytoestrogen-rich foods and dietary lignans with breast cancer risk. Dietary data were collected from 2,884 cases and 5,509 controls using a validated food-frequency questionnaire, which included additional questions phytoestrogen-rich foods. Associations were assessed using conditional logistic regression. All analyses were adjusted for relevant risk and confounding factors. Polytomous logistic regression analysis was performed to evaluate the associations by estrogen receptor (ER) status. High and low consumption of soybeans as well as of sunflower and pumpkin seeds were associated with significantly reduced breast cancer risk compared to no consumption (OR = 0.83, 95% CI = 0.70-0.97; and OR = 0.66, 95% CI = 0.77-0.97, respectively). The observed associations were not differential by ER status. No statistically significant associations were found for dietary intake of plant lignans, fiber, or the calculated enterolignans. Our results provide evidence for a reduced postmenopausal breast cancer risk associated with increased consumption of sunflower and pumpkin seeds and soybeans.

Topics: 4-Butyrolactone; Aged; Breast Neoplasms; Carcinoma; Case-Control Studies; Cucurbita; Diet; Dietary Fiber; Female; Germany; Glycine max; Helianthus; Humans; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Risk; Seeds

Phytoestrogens are found in foods such as soy (isoflavones) and flaxseed (lignans), and certain botanical supplements. Their role in estrogen receptor positive (ER+) breast cancer recurrence and treatment is controversial, and it is unknown how this affects intake among patients. The Ontario Cancer Registry was used to identify 417 population-based breast cancer cases (mean time from diagnosis was 57 days). A questionnaire was mailed to determine intake of phytoestrogen foods and supplements in the last 2 mo, changes since diagnosis and differences by ER tumor status or hormonal treatment. Of 278 (67%) respondents, 56% consumed soy foods, 39% consumed isoflavone-rich foods (tofu, soybeans, soy milk, soy nuts), and 70% ate lignan-rich foods, including flaxseed (33%). Only soy milk, flaxseed, and flaxseed bread were commonly consumed more than once/wk. Few patients (4%) took isoflavone (soy, red clover, kudzu, licorice, isoflavones) or lignan/flaxseed supplements. Since diagnosis, 17% started or stopped soy foods (most stopped); this was more prevalent among those receiving hormonal treatment (20%; 95% confidence interval (CI): 14, 26) than not (6%; 95% CI: 1, 12). No other differences by ER status or hormonal treatment were observed. Research is needed to confirm this and to explore influencing factors.

Topics: Adult; Aged; Breast Neoplasms; Diet; Dietary Supplements; Female; Flax; Humans; Isoflavones; Lignans; Middle Aged; Ontario; Phytoestrogens; Registries; Seeds; Soy Foods; Surveys and Questionnaires; Young Adult

Er Zhi Wan (EZW), a Chinese medicinal preparation, has been used clinically for treating menopausal syndrome for its kidney-invigorating function, which contains simply two herbs, Ecliptae Herba (EH) and Ligustri Lucidi Fructus (LLF). Although this herbal extract has been used for many years, there is no scientific basis about its effectiveness on menopausal symptom. Here, we aimed to evaluate the estrogenic activities of EZW and to study the compatibilities of two herbs including different processed-LLF in single and mixed preparation of EZW. Moreover, the weight ratio of EH to LLF in EZW was determined according to their estrogenic activities.. The extractions of LLF, processed-LLF and EH were prepared separately by extracting the powders with water, 50% alcohol or 95% alcohol. Steamed-LLF and EH were extracted separately, or together, in preparing EZW extracts. A promoter-reporter construct (pERE-Luc) containing three repeats of estrogen responsive elements (ERE) was stably transfected into MCF-7 cells, and this stable breast cancer cell line was used to determine the estrogenic property. The cell proliferation was measured by MTT assay.. The results showed that EZW could significantly induce the expression of luciferase driven by an estrogen responsive element in a pERE-Luc vector. The proliferation of MCF-7 cells was not altered by this herbal treatment. The best preparation of EZW was from: (i) LLF was firstly steamed over water and then dried to make steamed-LLF; and (ii) steamed-LLF and EH were extracted separately by 95% alcohol and then mixed together according to a weight ratio of 1:1.. Under the optimized extracting method, EZW possessed robust effect in activating the estrogenic activity, but which did not alter the proliferation of cultured MCF-7 cells. Thus, EZW is an effective and safe estrogenic herbal extract.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Eclipta; Female; Genetic Vectors; Humans; Ligustrum; MCF-7 Cells; Menopause; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Transfection

Formononetin is one of the main active components of red clover plants, and considered as a phytoestrogen. Its pharmacological effects in vivo may be either estrogenic or anti-estrogenic, mainly depending upon the estrogen levels. Our recent studies suggested that formononetin inactivated IGF1/IGF1R-PI3K/Akt pathways and decreased cyclin D1 mRNA and protein expression in human breast cancer cells in vitro and in vivo. In the present study, we further investigated the molecular mechanisms involved in the induced apoptosis effect of formononetin on breast cancer cells. Our results suggested that formononetin inhibited the proliferation of ER-positive MCF-7 cells and T47D cells. In contrast, formononetin could not inhibit the cell of growth of ER-negative breast cancer cells such as MDA-MB-435 S cells. We further found that formononetin activated MAPK signaling pathway in a dose-dependent manner, which resulted in the increased ratio of Bax/Bcl-2, and induced apoptosis on MCF-7 cells. However, when MCF-7 cells were pretreated with p38MAPK inhibitor SB203580 before formononetin, apoptosis induced by formononetin was significantly attenuated. Thus, we conclude that the induced apoptosis effect of formononetin on human breast cancer cells were related to Ras-p38MAPK pathway. Considering that red clover plants are widely used clinically, our results provide the foundation for future development of formononetin for treatment of ER-positive breast cancer.

Topics: Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Isoflavones; p38 Mitogen-Activated Protein Kinases; Phytoestrogens; Proto-Oncogene Proteins c-bcl-2; ras Proteins; Receptors, Estrogen

Dietary soy is thought to be cancer-preventive; however, the beneficial effects of soy on established breast cancer is controversial. We recently demonstrated that dietary daidzein or combined soy isoflavones (genistein, daidzein, and glycitein) increased primary mammary tumor growth and metastasis. Cancer-promoting molecules, including eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E, were up-regulated in mammary tumors from mice that received dietary daidzein. Herein, we show that increased eIF expression in tumor extracts of mice after daidzein diets is associated with protein expression of mRNAs with internal ribosome entry sites (IRES) that are sensitive to eIF4E and eIF4G levels. Results with metastatic cancer cell lines show that some of the effects of daidzein in vivo can be recapitulated by the daidzein metabolite equol. In vitro, equol, but not daidzein, up-regulated eIF4G without affecting eIF4E or its regulator, 4E-binding protein (4E-BP), levels. Equol also increased metastatic cancer cell viability. Equol specifically increased the protein expression of IRES containing cell survival and proliferation-promoting molecules and up-regulated gene and protein expression of the transcription factor c-Myc. Moreover, equol increased the polysomal association of mRNAs for p 120 catenin and eIF4G. The elevated eIF4G in response to equol was not associated with eIF4E or 4E-binding protein in 5' cap co-capture assays or co-immunoprecipitations. In dual luciferase assays, IRES-dependent protein synthesis was increased by equol. Therefore, up-regulation of eIF4G by equol may result in increased translation of pro-cancer mRNAs with IRESs and, thus, promote cancer malignancy.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Dietary Supplements; Equol; Eukaryotic Initiation Factor-4E; Eukaryotic Initiation Factor-4G; Female; Gene Expression Regulation, Neoplastic; Glycine max; Humans; Isoflavones; Mice; Mice, Nude; Neoplasm Transplantation; Phytoestrogens; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; RNA, Messenger; RNA, Neoplasm; Transplantation, Heterologous; Up-Regulation

To search for new targets of anticancer therapies using phytoestrogens we performed comparative metabolic profiling of the breast cancer cell line MCF-7 and the non-tumorigenic breast cell line MCF-12A. Application of gas chromatography-mass spectrometry (GC-MS) revealed significant differences in the metabolic levels after exposure with 17ß-estradiol, genistein or a composition of phytoestrogens within a native root flax extract. We observed the metabolites 3-(4-hydroxyphenyl)-lactic acid, cis-aconitic acid, 11-beta-hydroxy-progesterone, chenodeoxycholic acid and triacontanoic acid with elevated levels due to estrogen action. Particularly highlighted were metabolites of the sphingolipid metabolism. Sphingosine and its dihydro derivate as well as ethanolaminephosphate were significantly altered after exposure with 1 nM 17ß-estradiol in the cell line MCF-7, while MCF-12A was not affected. Treatment with genistein and the flax extract normalized the sphingosine concentrations to the basic levels found in MCF-12A cells. We could further demonstrate that the expression levels of the sphingosine metabolizing enzymes: sphingosine-1-phosphate kinase (Sphk) and lyase (S1P lyase) were significantly influenced by estrogens as well as phytoestrogens. The isoform Sphk2 was overexpressed in the tumorigenic cell line MCF-7, while S1P lyase was predominantly expressed in the non-tumorigenic cell line MCF-12A. Importantly, in MCF-7 the weak S1P lyase expression could be significantly increased after exposure with 10 µM genistein and 1 µg/ml root flax extract. Here, we present, for the first time, an analysis of metabolic response of phytoestrogens to breast cancer cell lines. The contrasting regulation of sphingolipid enzymes in MCF-7 and MCF-12A render them as preferred targets for future anticancer strategies.

Topics: Aldehyde-Lyases; Breast; Breast Neoplasms; Cell Line; Cell Line, Tumor; Estradiol; Female; Genistein; Humans; Metabolome; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor); Phytoestrogens; Sphingosine

Sex hormone replacement therapy provides several advantages in the quality of life for climacteric women. However, estrogen-induced cell proliferation in the uterus and mammary gland increases the risk of cancer development in these organs. The lower incidence of mammary cancer in Asian women as compared with Western women has been attributed to high intake of soy isoflavones, including genistein. We have previously shown that genistein induces an estradiol-like hypertrophy of uterine cells, but does not induce cell proliferation, uterine eosinophilia, or endometrial edema. It also inhibits estradiol-induced mitosis in uterine cells and hormone-induced uterine eosinophilia and endometrial edema. Nevertheless, genistein stimulates growth of human breast cancer cells in culture; therefore, it is not an ideal estrogen for use in hormone replacement therapy (HRD). The present study investigated the effect of another soy isoflavone, daidzein (subcutaneous, 0.066 mg/kg body weight), in the same animal model, and its effect on responses induced by subsequent treatment (1 h later) with estradiol-17β (E(2); subcutaneous, 0.33 mg/kg body weight). In addition, we investigated the effects of daidzein (1 μg/mL) or E(2) on the growth of human breast cancer cells in culture. Results indicate that daidzein stimulates growth of breast cancer cells and potentiates estrogen-induced cell proliferation in the uterus. We suggest caution for the use of daidzein or formulas containing this compound in HRD. Future research strategies should be addressed in the search for new phytoestrogens that selectively inhibit cell proliferation in the uterus and breast.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Interactions; Estradiol; Estrogens; Female; Glycine max; Humans; Isoflavones; MCF-7 Cells; Phytoestrogens; Plant Extracts; Rats; Rats, Sprague-Dawley; Uterus

Phytooestrogens are known to cause anti-cancer effects on mamma carcinoma cells. In this study, the effects of the lignan secoisolariciresinol and the isoflavone glycosides and aglycones genistein, genistin, daidzein and daidzin were tested on MCF-7 and BT20 cells in vitro.. First, the cellular expression of hormone receptors was examined by immunohistochemical procedures. The effects of the phytooestrogens on the cells were detected by using three different assays measuring cell letality, viability and proliferation. The phytooestrogens were tested in concentrations of 1, 5, 10 and 50 μg/mL, respectively. 17β-oestradiol and tamoxifen were used as controls, respectively, in the same concentrations as the phytooestrogens.. The immunohistochemistry showed evidence of oestrogen- and progesterone receptors at the MCF-7 cell line, whereas no expression could be seen at the BT20 cells. Among the phytooestrogens, genistein and secoisolariciresinol showed various anti-cancerogenic effects on both cell lines, respectively, but only in the highest concentration. Regarding the controls, tamoxifen showed a stronger antivital and anti-proliferative effect on BT20 than on MCF-7. Oestradiol caused sporadic anti-cancer effects on both cell lines, respectively, at its highest concentration.. Genistein and Secoisolariciresinol have anti-cancer properties on MCF-7 and BT20 in vitro. There are differences in the effects of isoflavones depending on the glycolysation status. The role of the oestrogen receptors in the mechanisms of action of both the phytooestrogens and controls is of less importance. Further investigations have to be carried out, especially concerning the mechanisms of action. Phytooestrogens may be potential substances in the therapy of mamma carcinomas.

Topics: Breast Neoplasms; Butylene Glycols; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Genistein; Humans; Immunohistochemistry; Isoflavones; L-Lactate Dehydrogenase; Lignans; Phytoestrogens; Receptors, Estrogen; Receptors, Progesterone

The present study addresses, by transcriptomics and quantitative stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics, the estrogen receptor α (ERα) and β (ERβ)-mediated effects on gene and protein expression in T47D breast cancer cells exposed to the phytoestrogen genistein. Using the T47D human breast cancer cell line with tetracycline-dependent ERβ expression (T47D-ERβ), the effect of a varying intracellular ERα/ERβ ratio on genistein-induced gene and protein expression was characterized. Results obtained reveal that in ERα-expressing T47D-ERβ cells with inhibited ERβ expression genistein induces transcriptomics and proteomics signatures pointing at rapid cell growth and migration by dynamic activation of cytoskeleton remodeling. The data reveal an interplay between integrins, focal adhesion kinase, CDC42, and actin cytoskeleton signaling cascades, occurring upon genistein treatment, in the T47D-ERβ breast cancer cells with low levels of ERα and no expression of ERβ. In addition, data from our study indicate that ERβ-mediated gene and protein expression counteracts ERα-mediated effects because in T47D-ERβ cells expressing ERβ and exposed to genistein transcriptomics and proteomics signatures pointing at a clear down-regulation of cell growth and induction of cell cycle arrest and apoptosis were demonstrated. These results suggest that ERβ decreases cell motility and metastatic potential as well as cell survival of the breast cancer cell line. It is concluded that the effects of genistein on proteomics and transcriptomics end points in the T47D-ERβ cell model are comparable with those reported previously for estradiol with the ultimate estrogenic effect being dependent on the relative affinity for both receptors and on the receptor phenotype (ERα/ERβ ratio) in the cells or tissue of interest.

Topics: Breast Neoplasms; Cell Line, Tumor; Cluster Analysis; Enzyme-Linked Immunosorbent Assay; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genistein; Humans; Phytoestrogens; Proteome; Proteomics; Signal Transduction

Sesame lignans (sesamin, sesamolin) and their metabolites (enterodiol, ED; enterolactone, EL; and sesamol) have been evaluated for their estrogenic activities. ED and EL have been indicated to have estrogenic/antiestrogenic properties on human breast cancer cells; however the estrogenic activities of sesamin, sesamolin and sesamol have not been reported. In the present study, estrogenic potencies of sesame lignans and their metabolites were determined by estrogen responsive element (ERE) luciferase reporter assay in T47D cells stably transfected with ERE-luc (T47D-KBluc cells) and quantifying pS2 and progesterone receptor gene expression in T47D cells. All tested compounds except ED possessed ability of ERE activation with a very low potency compared to estradiol (E2). These effects were abolished by coincubating tested compounds with 1 μM ICI 182 780, suggesting that estrogen receptors were directly involved in their ERE activations. Among tested compounds, sesamol showed the highest ability in ERE induction. The coincubation of increasing concentration of E2 (10(-12)-10(-6) M) with 10 μM of tested compounds resulted in a downward shift of E2-ERE dose-response curves. In contrast, at the low concentration of E2 (10(-12) M), sesamin and sesamol significantly exhibited additive effects on the E2 responses. The inhibitory effect in a dose-dependent manner was also observed when 1-100 μM sesamol was coincubated with 1 nM E2. Sesamin, sesamol and EL significantly induced pS2 gene expression whereas only sesamol could significantly induce progesterone receptor gene. The data obtained in this study suggested that sesame lignans and their metabolites possess weak estrogenic/antiestrogenic activity.

Topics: Breast Neoplasms; Cell Line, Tumor; Estrogen Receptor Modulators; Female; Gene Expression Regulation, Neoplastic; Humans; Lignans; Phytoestrogens; Plant Extracts; Receptors, Estrogen; Sesamum

Two species of Thai medicinal plants, Dalbergia parviflora R. (Leguminosae) and Belamcanda chinensis L. (Iridaceae), used traditionally for the regulation of menstrual disorders, have been found to contain a large number of potential estrogen-like compounds. A set of some 55 isolated isoflavonoids and diphenolics showed a wide range of estrogen activity as determined in breast cancer MCF-7 and T47D cell proliferation assays. This set of compounds was studied by means of computational techniques including quantitative structure-activity relationships (QSAR) and molecular modeling. It was found that the estrogenic potencies of the studied compounds depend mainly upon the presence/absence of hydroxyl groups attached to 3' and 5' positions of B ring of the isoflavone scaffold and the inter-atomic distance between the hydroxyl groups attached to the outer terminal positions 7 of A ring and 4' of B ring. In a QSAR model employing ligand-receptor interaction energy descriptors, the LigScore scoring function of Cerius(2) virtual screening module, which describes the receptor affinities of simultaneous binding to estrogenic receptors α and β (ER(α) and ER(β)), led to the best correlation between the observed estrogenic activities and computed descriptors. Consideration of independent binding to ER(α) and ER(β) did not result in statistically significant QSAR models. It was thus concluded that simultaneous and possibly competitive interaction of the compounds with the ER(α) and ER(β) receptors, in which the presence of hydroxyl groups at the abovementioned positions of the isoflavonoids and diphenolics molecular scaffold plays a dominant role, may determine the estrogenic potency of the considered phytochemicals.

Topics: Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Dalbergia; Female; Flavonoids; Humans; Hydroxyl Radical; Iridaceae; Isoflavones; Models, Molecular; Phytoestrogens; Plant Extracts; Plants, Medicinal; Quantitative Structure-Activity Relationship; Receptors, Estrogen; Thailand

The objective of the present study was to determine the effects of soya and whey milk protein, α-lactalbumin (α-LA), on mammary gland morphology and the structural support of the gland, in pre-pubertal mice after 7 d of treatment. In Expt 1, weaned (day 21) CD1 mice were given one of the four treatments, three included dietary supplements: (1) control diet, casein, (2) soya, (3) α-LA and (4) subcutaneous injection of 2·5 μg oestradiol benzoate in 20 μl maize oil and fed the control diet. All diets were isoenergetic with equal protein concentrations. All groups that were not treated with oestradiol received the vehicle. Whole-mount analyses were performed to determine longitudinal ductal growth and terminal end bud development. DNA was extracted from the gland and assessed by spectrophotometry (260/280 nm). Tissue extracts for extracellular matrix (ECM) proteins, matrix metalloproteinase-2 (MMP(2)), tissue inhibitor of MMP(2) (TIMP(2)), and serum oestradiol and mammary tissue epidermal growth factors (EGF) were measured by immunoassays. Expt 2 utilised the Her2/neu transgenic strain, with the same protocols. Statistical significance was determined by one-way ANOVA. From Expt 1 and 2, soya and α-LA significantly increased ductal elongation when compared with the oestrogen and control groups. These results were corroborated by data on total DNA and the ratio of MMP(2):TIMP(2). The ratio of MMP(2):TIMP(2) was affected by α-LA. Serum oestradiol was decreased only in the oestradiol-treated groups in both experiments. Soya is known to be oestrogenic and can act on epithelia directly. The mechanism by which α-LA affects glandular development is by modulating the ECM or by promoting the synthesis/activity of EGF.

Topics: Animals; Breast Neoplasms; Caseins; DNA; Epidermal Growth Factor; Estradiol; Estrogens, Non-Steroidal; Extracellular Matrix Proteins; Female; Lactalbumin; Mammary Glands, Animal; Matrix Metalloproteinase 2; Mice; Mice, Transgenic; Milk Proteins; Phytoestrogens; Random Allocation; Receptor, ErbB-2; Soybean Proteins; Tissue Inhibitor of Metalloproteinase-2; Weaning; Whey Proteins

In this study, we investigated the underlying mechanism by which phytoestrogens suppress the growth of normal (MCF-10A) and malignant (MDA-MB-231) estrogen receptor α (ERα)-negative breast cells. We hypothesized that phytoestrogen inhibits the proliferation of ERα-negative breast cancer cells. We found that all tested phytoestrogens (genistein, apigenin, and quercetin) suppressed the growth of both MCF-10A and MDA-MB-231 cells, as revealed by proliferation assays. These results were accompanied by an increase in the sub-G0/G1 apoptotic fractions as well as an increase in the cell population in the G2/M phase in both cell types, as revealed by cell cycle analysis. When we assessed the effect of phytoestrogens on the level of intracellular signaling molecules by Western blot analysis, we found that phytoestrogens increased the level of active p53 (phospho-p53) without changing the p53 level in both MCF-10A and MDA-MB-231 cells. Phytoestrogens also induced an increase in p21, a p53 target gene, and a decrease in either Bcl-xL or cyclin B1 in both cell types. In contrast, the protein levels of phosphatase and tensin homolog, cyclin D1, cell division control protein 2 homolog, phospho-cell division control protein 2 homolog, and p27 were not changed after phytoestrogen treatment. Our data indicate that phytoestrogens induce apoptotic cell death of ERα-negative breast cancer cells via p53-dependent pathway and suggest that phytoestrogens may be promising agents in the treatment and prevention of ERα-negative breast cancer.

Topics: Apigenin; Apoptosis; Breast; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Estrogen Receptor alpha; Female; G2 Phase; Gene Expression Regulation, Neoplastic; Genistein; Humans; Phytoestrogens; Quercetin; Tumor Suppressor Protein p53; Up-Regulation

To study the inhibition effect of equol on MDA-MB-231 cells, a human breast cancer cell line with estrogen-independent receptor.. Cultured MDA-MB-231 cells were treated with different contents of equol. The cell viability was assessed with MTT method. The apoptosis was detected by flow cytometry and immunofluorescence. Western Blot was used to assess the expression of NF-kappaB.. The growth of MDA-MB-231 cells was inhibited by equol in a does-and time-dependent manner. The apoptosis of MDA-MB-231 cells induced by equol was the result of inhibiting the expression of NF-kappaB.. The apoptosis of MDA-MB-231 cells might be the reduced expression of NF-kappaB induced by equol.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Equol; Female; Humans; NF-kappa B; Phytoestrogens

Calycosin is one of main components in the herb radix astragali and is considered a typical phytoestrogen. It has either estrogenic or antiestrogenic effects that mainly depend on estrogen levels in vivo. This study investigated the effects and mechanisms of calycosin on estrogen receptor (ER)-positive human breast cancer (MCF-7) cells in vitro.. ER-positive MCF-7 cells were treated with different concentrations of calycosin. Effects of calycosin on the proliferation of ER-positive MCF-7 cells were determined by the MTT assay. Apoptosis in these treated cells was examined by flow cytometry. The mRNA and protein levels of Bcl-2 and Bax in these treated cells were also determined by reverse-transcription polymerase chain reaction and immunohistochemical staining, respectively.. Compared with the vehicle control, calycosin stimulated proliferation of ER-positive MCF-7 cells at low concentrations (2, 4, and 8 µmol/L). Furthermore, at these concentrations, calycosin decreased the percentage of early apoptosis in MCF-7 cells, downregulated mRNA and protein levels of Bax, and upregulated those of Bcl-2 at low concentrations. On the other hand, calycosin at higher concentrations (16 and 32 µmol/L) inhibited cell proliferation.. At relatively low concentrations, calycosin has stimulatory effects on the proliferation of MCF-7 cells, with the estrogenic effect the mechanism.

Topics: Astragalus Plant; bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Female; Gene Expression; Genes, bcl-2; Humans; Isoflavones; Phytoestrogens; Plant Extracts; Plant Roots; Proto-Oncogene Proteins c-bcl-2; Receptors, Estrogen

Phytoestrogens are known to prevent tumor induction. But their molecular mechanisms of action are largely unknown. This study aimed to examine the effect of genistein and quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells.. The antiproliferative effects of phytoestrogens were tested by proliferation assays. Flow cytometry was performed to analyze the cell cycle. The effect of phytoestrogens on cell-signaling molecules was determined by Western blotting.. Genistein and quercetin inhibited the proliferation of MCF-7 vec and MCF-7 HER2 cells. This growth inhibition was accompanied with an increase of subG(0)/G(1) apoptotic fractions. Genistein and quercetin induced extrinsic apoptosis pathway, up-regulating p53. Genistein and quercetin reduced the phosphorylation level of IκBα, and abrogated the nuclear translocation of p65 and its phosphorylation within the nucleus.. Genistein and quercetin exert their antiproliferative activity by inhibiting NFκB signaling. Phytoestrogens could be potential useful compounds to prevent or treat HER2-overexpressing breast cancer.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p16; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Extracellular Signal-Regulated MAP Kinases; Female; Genistein; Humans; JNK Mitogen-Activated Protein Kinases; Mitochondria; Models, Biological; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Phytoestrogens; Proto-Oncogene Proteins c-akt; Quercetin; Receptor, ErbB-2; Signal Transduction; Tumor Suppressor Protein p53

It remains unclear whether estrogenic botanical supplement (EBS) use influences breast cancer survivors' health-related outcomes.. We examined the associations of EBS use with health-related quality of life (HRQOL), with fatigue, and with 15 hormone-related symptoms such as hot flashes and night sweats among 767 breast cancer survivors participating in the Health, Eating, Activity, and Lifestyle (HEAL) Study. HRQOL was measured by the Medical Outcomes Study short form-36 physical and mental component scale summary score. Fatigue was measured by the Revised-Piper Fatigue Scale score.. Neither overall EBS use nor the number of EBS types used was associated with HRQOL, fatigue, or hormone-related symptoms. However, comparisons of those using each specific type of EBS with non-EBS users revealed the following associations. Soy supplements users were more likely to have a better physical health summary score (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.02-2.70). Flaxseed oil users were more likely to have a better mental health summary score (OR = 1.76, 95% CI = 1.05-2.94). Ginseng users were more likely to report severe fatigue and several hormone-related symptoms (all ORs ≥ 1.7 and all 95% CIs exclude 1). Red clover users were less likely to report weight gain, night sweats, and difficulty concentrating (all OR approximately 0.4 and all 95% CIs exclude 1). Alfalfa users were less likely to experience sleep interruption (OR = 0.28, 95% CI = 0.12-0.68). Dehydroepiandrosterone users were less likely to have hot flashes (OR = 0.33, 95% CI = 0.14-0.82).. Our findings indicate that several specific types of EBS might have important influences on a woman's various aspects of quality of life, but further verification is necessary.

Topics: Adult; Breast Neoplasms; Dietary Supplements; Fatigue; Female; Hot Flashes; Humans; Middle Aged; Phytoestrogens; Phytotherapy; Plant Preparations; Prospective Studies; Quality of Life; Survivors; Sweating

The aim of this study was to determine whether the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway is involved in genistein- and equol-induced cell proliferation and estrogen receptor (ER) alpha transactivation. For MCF-7 human breast cells, low concentrations of genistein and equol enhanced proliferation and induced MCF-7 cells to enter the S-phase. Genistein- and equol-induced cell proliferation and S-phase entry were blocked by the ERalpha antagonists 4-hydroxytamoxifen and ICI 182,780 and by the mitogen-activated protein kinase 1/2 inhibitor U0126. These data indicated that ERalpha and mitogen-activated protein extracellular kinase/ERK signaling were required for the effects of genistein/equol on cell growth and cell cycle progression. Genistein and equol induced delayed and prolonged activation of ERK1/2. Inhibition of ERK1/2 phosphorylation by U0126 led to complete suppression of genistein- and equol-induced estrogen response element reporter activity and to suppression of the estrogen-responsive gene pS2. The anti-estrogen ICI had no effect on genistein- and equol-induced ERK1/2 phosphorylation. These results suggest that activation of ERK1/2 lies upstream of ER-mediated transcription, and that ERK1/2 activation is necessary for the transactivation of ERalpha. In conclusion, genistein and equol elicit a delayed activation of ERK1/2, and this activation appears to be involved in the proliferation of breast cancer cells and estrogen-dependent transcriptional activation.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Equol; Estrogen Antagonists; Estrogen Receptor alpha; Extracellular Signal-Regulated MAP Kinases; Female; Genes, Reporter; Genistein; Humans; Isoflavones; Phosphorylation; Phytoestrogens; Protein Processing, Post-Translational; Time Factors; Transcriptional Activation

The seed of Psoralea corylifolia L. (PCL), a well-known traditional Chinese medicine, has been applied as a tonic or an aphrodisiac agent and commonly used as a remedy for bone fracture, osteomalacia and osteoporosis in China. In our study, the estrogen receptor subtype-selective activities of the extracts and compounds derived from PCL were analyzed using the HeLa cell assay. The different fractions including petroleum ether, CH(2)Cl(2) and EtOAc fractions of the EtOH extract of PCL showed significant activity in activating either ERalpha or ERbeta whereas the n-BuOH fraction showed no estrogenic activity. Further chromatographic purification of the active fractions yielded seven compounds including the two coumarins isopsoralen and psoralen, the four flavonoids isobavachalcone, bavachin, corylifol A and neobavaisoflavone, and the meroterpene phenol, bakuchiol. In reporter gene assay, the two coumarins (10(-8)-10(-5)M) acted as ERalpha-selective agonists while the other compounds (10(-9)-10(-6)M) activated both ERalpha and ERbeta. The estrogenic activities of all compounds could be completely suppressed by the pure estrogen antagonist, ICI 182,780, suggesting that the compounds exert their activities through ER. Only psoralen and isopsoralen as ERalpha agonists promoted MCF-7 cell proliferation significantly. Although all the compounds have estrogenic activity, they may exert different biological effects. In conclusion, both ER subtype-selective and nonselective activities in compounds derived from PCL suggested that PCL could be a new source for selective estrogen-receptor modulators.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Ficusin; Flavones; Flavonoids; Furocoumarins; HeLa Cells; Humans; Isoflavones; Medicine, Chinese Traditional; Phenols; Phytoestrogens; Plant Extracts; Psoralea; Seeds; Selective Estrogen Receptor Modulators

Phytoestrogens have attracted attention as being safer alternatives to hormone replacement therapy (HRT) and as chemopreventive reagents for breast cancer because dietary soy isoflavone intake has been correlated with reduction in risk. To identify safe and effective phytoestrogen candidates for HRT and breast cancer prevention, we investigated the effects of daidzein, genistein, coumestrol, resveratrol and glycitein on cell growth, cell cycle, cyclin D1 expression, apoptosis, Bcl-2/Bax expression ratio and p53-dependent or NF-kappaB-dependent transcriptional activity in MCF-7 breast cancer cells. Phytoestrogens, except for glycitein, significantly enhanced estrogen-response-element-dependent transcriptional activity up to a level similar to that of 17beta-estradiol (E(2)). E(2) increased cell growth significantly, coumestrol increased cell growth moderately, and resveratrol and glycitein reduced cell growth. Phytoestrogens, except for glycitein, stimulated the promotion of cells to G(1)/S transition in cell cycle analysis, similar to E(2). This stimulation was accompanied by transient up-regulation of cyclin D1. While genistein, resveratrol and glycitein all increased apoptosis and reduced the Bcl-2/Bax ratio, resveratrol reduced this ratio more than either genistein or glycitein. Moreover, resveratrol significantly enhanced p53-dependent transcriptional activity, but slightly reduced NF-kappaB-dependent transcriptional activity. On knockdown analysis, genistein, resveratrol and glycitein all reduced the Bcl-2/Bax ratio in the presence of apoptosis-inducing stimuli, and estrogen receptor (ER) alpha silencing had no effect on these reductions. In contrast, in the absence of apoptosis-inducing stimuli, only resveratrol reduced the ratio, and ERalpha silencing abolished this reduction. Thus, resveratrol might be the most promising candidate for HRT and chemoprevention of breast cancer due to its estrogenic activity and high antitumor activity.

Topics: Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Coumestrol; Estradiol; Estrogen Receptor alpha; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes

In order to study the anticancer effects and cellular apoptosis pathways induced by daidzein.. We used the human MCF-7 breast cancer cell line as a model and examined the apoptosis by Hoechst-propidium iodide staining fluorescence imaging and flow cytometry.. Our data indicated that daidzein induces antiproliferative effects in a concentration- and time-dependent manner. We demonstrated that daidzein-induced apoptosis in MCF-7 cells was initiated by the generation of reactive oxygen species (ROS). Furthermore, we showed that this daidzein-induced ROS generation was accompanied by disruption of mitochondrial transmembrane potential, down-regulation of bcl-2, and up-regulation of bax, which led to the release of cytochrome C from the mitochondria into the cytosol, which, in turn, resulted in the activation of caspase-9 and caspase-7, and ultimately in cell death. The induction of the mitochondrial caspase-dependent pathway was confirmed by pretreatment with pan-caspase inhibitor z-VAD-fmk and antioxidant N-acetyl-L-cysteine.. Accordingly, daidzein could induce breast cancer cell apoptosis through the mitochondrial caspase-dependent cell death pathway.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Isoflavones; Membrane Potential, Mitochondrial; Mitochondria; Phytoestrogens; Reactive Oxygen Species; Signal Transduction; Time Factors; Up-Regulation

The characterization of phytoestrogen intake and cancer risk has been hindered by the absence of accurate dietary phytoestrogen values.. We examined the risk of breast, colorectal, and prostate cancers relative to phytoestrogen intake on the basis of a comprehensive database.. Demographic and anthropometric characteristics, a medical history, and 7-d records of diet were collected prospectively from participants (aged 40-79 y) in the European Prospective Investigation into Cancer and Nutrition-Norfolk (EPIC-Norfolk). Five hundred nine food items were analyzed by liquid chromatography-mass spectrometry/mass spectrometry, and (13)C(3)-labeled internal standards were analyzed for isoflavones (genistein, daidzein, glycitein, biochanin A, and formononetin), lignans (secoisolariciresinol and matairesinol), and enterolignans from gut microbial metabolism in animal food sources (equol and enterolactone). From the direct analysis, values for 10,708 foods were calculated. Odds ratios (ORs) for breast (244 cases, 941 controls), colorectal (221 cases, 886 controls), and prostate (204 cases, 812 controls) cancers were calculated relative to phytoestrogen intake.. Phytoestrogen intake was not associated with breast cancer among women or colorectal cancer among men. Among women, colorectal cancer risk was inversely associated with enterolactone (OR: 0.33; 95% CI: 0.14, 0.74) and total enterolignans (OR: 0.32; 95% CI: 0.13, 0.79), with a positive trend detected for secoisolariciresinol (OR: 1.60; 95% CI: 0.96, 2.69). A positive trend between enterolignan intake and prostate cancer risk (OR: 1.27; 95% CI: 0.97, 1.66) was attenuated after adjustment for dairy intake (OR: 1.19; 95% CI: 0.77, 1.82).. Dietary phytoestrogens may contribute to the risk of colorectal cancer among women and prostate cancer among men.

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Female; Gas Chromatography-Mass Spectrometry; Humans; Incidence; Isoflavones; Lignans; Logistic Models; Male; Middle Aged; Phytoestrogens; Prospective Studies; Prostatic Neoplasms; Risk Factors; Spectrometry, Mass, Electrospray Ionization; United Kingdom

Phytoestrogens (PEs) are naturally occurring plant components produced in a large range of plants. They can induce biologic responses in vertebrates by mimicking or modulating the action or production of endogenous hormones. This study examined mixtures of 12 food relevant PEs for effects on steroid hormone production, aromatase activity, estrogenic activity, and for interaction with the androgen receptor. The results show that a mixture of all tested PEs increased estradiol production and decreased testosterone production in H295R human adrenal corticocarcinoma cells, indicating an induced aromatase activity. Furthermore, exposure of the H295R cells to isoflavonoids caused a decrease in testosterone production, and various mixtures of PEs significantly stimulated MCF-7 human breast adenocarcinoma cell growth and induced aromatase activity in JEG-3 choriocarcinoma cells. The estrogenic effect in the MCF7 cells of the isoflavonoid mixture and coumestrol was supported by an observed increase in progesterone receptor protein expression as well as a decreased ERalpha expression. Overall, the results support that nutrition-relevant concentrations of PEs both alone and in mixtures possess various endocrine disrupting effects, all of which need to be considered when assessing the effects on human health.

Topics: Adrenal Cortex Neoplasms; Aromatase; Breast Neoplasms; Cell Division; Cell Line, Tumor; Endocrine Disruptors; Estradiol; Estrogen Receptor alpha; Estrogens; Flavonoids; Food; Humans; Phytoestrogens; Plants, Edible; Receptors, Androgen; Receptors, Progesterone; Steroids; Testosterone

Breast cancer is a public health problem in the Western countries. Several studies have shown that BRCA2, like BRCA1 oncosuppressors, are strongly involved in hereditary and sporadic mammary carcinogenesis. It has also been suggested that soy has a protective effect against breast cancer in Asia and, more particularly, phytoestrogens such as daidzein and genistein. Thus, phytoestrogens may have an impact on the expression of BRCA2 gene, and there is a possible link between BRCA2 and genes acting around the BRCA2. To focus on these processes, we set up the BRCA2 specific knockdown by RNA interference in two breast tumor cell lines (MCF-7 and MDA-MB-231) and also in a non-tumorigenic breast cell line (MCF-10a). After inhibition of BRCA2 expression, cells were maintained in different conditions and treated with either daidzein or genistein or left untreated. Microarray analysis of mRNAs isolated from the BRCA2 knocked down MCF-7, MDA-MB-231, and MCF-10a cell lines after being treated with phytoestrogens showed 35 differentially expressed genes between positive-ERbeta cells and negative-ERbeta cells. After genistein or daidzein treatments, BRCA1 was found to be up-regulated when knocked down with BRCA2-siRNA MCF-7 and BRCA2 was found to be up-regulated when knocked down with BRCA2-siRNA MDA-MB 231 cells. In MCF-10a, we observed a significant decrease in BAX and BCL2 expressions with a greater effect of daidzein. We also found an increase in BRIP expression between genistein and daidzein treatment knocked down with BRCA2-siRNA MCF-7 and MDA-MB-231 cell lines.

Topics: bcl-2-Associated X Protein; Breast Neoplasms; Cell Line, Tumor; DNA-Binding Proteins; Fanconi Anemia Complementation Group Proteins; Female; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Genes, BRCA2; Genistein; Humans; Isoflavones; Phytoestrogens; Polymerase Chain Reaction; Receptors, Estrogen; RNA Helicases

Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.

Topics: Breast Neoplasms; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Estrogen Receptor beta; Fatty Acids; Humans; Isomerism; Linoleic Acids; Linoleic Acids, Conjugated; Linolenic Acids; Lythraceae; Phytoestrogens; Plant Oils; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Seeds; Selective Estrogen Receptor Modulators

Glyceollins, which are synthesized from daidzein in soybeans cultured with fungi, have been shown to have antifungal effects and cancer preventive properties. Several studies have proposed that isoflavones and their metabolites act as a mixed agonist/antagonist for estrogen. Although glyceollins were reported to suppress some cancer cells via anti-estrogenic activity, it is not clear whether the compounds possess estrogenic potential. In contrast to the anti-estrogenic action reported thus far, we observed estrogenic effects of glyceollins using E-screen assay and pS2 expression, whereas glyceollins showed higher affinity for estrogen receptor (ER) beta than ERalpha. We also found that glyceollins were more efficiently produced de novo in minced than in half-sliced soybean, following infection with Aspergillus sojae. In conclusion, glyceollins may be useful in the prevention or amelioration of postmenopausal complications because they had strong estrogenic activity, and their production could be variable depending upon processing prior to fungal inoculation.

Topics: Aspergillus; Breast Neoplasms; Cell Line, Tumor; Female; Glycine max; Humans; Phytoestrogens; Plant Preparations; Pterocarpans; Receptors, Estrogen; Seeds; Trefoil Factor-1; Tumor Suppressor Proteins

Phloridzin, a phloretin 2'-beta-D-glucoside, belongs to dihydrochalcones and mainly exists in the fruits of Malus pumila Mill., Lithocarpus polystachyus REHD and the root skins, stems, tender leaves and fruits of Malus hupehensis. It has many pharmacological activities, such as regulating blood sugar level and blood pressure, protecting heart, scavenging of oxygen free radicals and antioxidant injuries. Thus, market demand of products containing phloridzin is increasing year by year. Our research results demonstrated that phloridzin is provided with a double directional adjusting function of estrogenic and antiestrogenic activities. It showed significant effects on the proliferation of estrogen sensitive estrogen receptor (ER) (+)MCF-7 cells in the absence of estrogen. When added with 17beta-estradiol, phloridzin showed antagonism on estradiol-induced MCF-7 cell proliferation, but it did not significantly affect proliferation of estrogen insensitive ER (-)MDA-MB-231 cells. Phloridzin induced beta-galactosidase activity in a yeast two-hybrid assay. Light increase of the uterine weight and serum estradiol content of mouse was observed when the glucoside was administered orally for 7 d. After oral administration, phloridzin was found mainly in the blood and a small part was metabolized to phloretin. Our investigation proved that phloridzin was distributed at the target organ and played the role of phytoestrogen.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; beta-Galactosidase; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor Modulators; Estrogens; Fagaceae; Female; Glucosides; Humans; Malus; Mice; Mice, Inbred Strains; Organ Size; Phlorhizin; Phytoestrogens; Phytotherapy; Plant Extracts; Receptors, Estrogen; Tissue Distribution; Uterus; Yeasts

BRCA1 gene mutation is associated with a combination of excessive aromatase activity/expression, predominantly estrogen receptor-negative phenotypes of tumors, and only scarce information about estrogen contents in body fluids. In the present work, isotope dilution capillary gas chromatography/mass spectrometry was used to study urinary excretion of estrogens, their catechol metabolites, and phytoestrogens in 22 women (11 with BCRA1 gene mutations and 11 without these mutations) in average 5.1+/-0.4 years before surgery for breast cancer. BCRA1 mutation carriers (including 3 premenopausal females) compared with respective controls showed significantly higher urinary estradiol and estrone excretion and a trend to an increased 2-OH-E2 excretion. In the subgroup of untreated postmenopausal women, BCRA1 mutation carriers showed a trend to increased estradiol and estrone excretion and to a higher value of the mean levels of all estrogen metabolites tested. The treatment after the baseline laboratory investigation of 6 women from postmenopausal group with the antidiabetic biguanide metformin for 3 months was associated with decreases in the excretion rates of 4-hydroxyestradiol, 2-methoxyestradiol, and 16-epiestriol and did not influence phytoestrogen excretion. The decrease in 2-methoxyestrogen excretion was more consistent in women without BCRA1 mutations than in BCRA1 mutation carriers. The data suggest the possibility that aromatase complex activation in BCRA1 mutation carriers is combined with increases in both, estrogen metabolism into catecholestrogens and their inactivation by methoxylation, and that metformin may affect both of these pathways.

Topics: Breast Neoplasms; Estrogens; Estrogens, Catechol; Female; Gas Chromatography-Mass Spectrometry; Genes, BRCA1; Genetic Predisposition to Disease; Humans; Hypoglycemic Agents; Metformin; Middle Aged; Phytoestrogens; Pilot Projects; Postmenopause; Prognosis

Flaxseed (FS), an oilseed containing high amounts of the phytoestrogen lignan, secoisolariciresinol diglucoside (SDG), and n-3 fatty acid, alpha-linolenic acid-rich oil (FO), has been shown to inhibit the growth of established human breast tumors (MCF-7) in ovariectomized (OVX) athymic mice. However, the major FS component responsible for this effect and the mechanism(s) of its action are unclear. Hence, this study determined, in a 2 x 2 factorial design, the effect of SDG and FO, alone or in combination, on the growth of established human estrogen receptor positive (ER+) breast tumors and the potential mechanism(s) of its action. OVX mice with established ER+ human breast tumors (MCF-7) were treated for 8 wk with basal diet (BD, control) or BD supplemented with SDG (1 g/kg), FO (38.5 g/kg), or SDG + FO. All treatments reduced the tumor growth, but SDG had the greatest effect primarily through reducing tumor cell proliferation rather than increasing apoptosis. SDG had a main effect in the reduction of PS2, BCL2, and IGF-1R mRNA expression, whereas FO had a main effect only in PAKT reduction. SDG alone also lowered the ERalpha, ERbeta, EGFR, BCL2 mRNA, and PMAPK protein, indicating that its effect involves the modulation of the ER- and growth factor receptor-mediated signaling pathways.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Butylene Glycols; Female; Gene Expression Regulation, Neoplastic; Glucosides; Humans; Linseed Oil; Mice; Mice, Nude; Phytoestrogens; Phytotherapy; Proto-Oncogene Proteins; Receptors, Estrogen; Receptors, Growth Factor; RNA, Messenger; Signal Transduction; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

Although the rate of breast cancer differs between women in Asian and Western countries, molecular genetics/genomics basis of this epidemiological observation remains elusive. Moreover, the intake of phytoestrogens is associated with a lower incidence of breast cancer. Genistein and daidzein are the primary soy isoflavones with a chemical structure similar to estrogens. Conceivably, the actions of phytoestrogens on gene expression signatures might mediate their postulated effects on breast cancer pathogenesis. The present study evaluated the transcriptional responsiveness of breast cancer cells to soy phytoestrogens using a whole-genome microarray-based approach. Human breast cancer cell lines and a fibrocystic breast cell line were treated with genistein or daidzein. We identified 278 and 334 differentially expressed genes after genistein or daidzein treatment, respectively, in estrogen-positive (MCF-7) and estrogen-negative (MDA-MB-231, MCF-10a) cells. Hierarchical clustering of this finding revealed a significant modulation, respectively, of 246 or 169 genes after genistein or daidzein exposures. Importantly, the molecular pathways for the differentially expressed genes included those that relate to cell communication, biodegradation of xenobiotics, lipid metabolism, signal transduction, and cell growth/death. These molecular observations collectively contribute to a growing knowledgebase on the putative mechanism(s) of action of phytoestrogens in breast cancer pathogenesis and chemoprevention.

Topics: Breast Neoplasms; Cell Line, Tumor; Cells, Cultured; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genistein; Genome, Human; Humans; Isoflavones; Microarray Analysis; Molecular Sequence Data; Multigene Family; Phytoestrogens

Trigonella foenum graecum commonly known as fenugreek, has been widely cultivated in Asia, Africa and Mediterranean countries for the edible and medicinal values of its seeds. Earlier reports show that fenugreek seeds provide a mastogenic effect resulting in enhanced breast size. However, very little is known about its estrogenic effect. The present study investigated the effect of chloroform extracts of fenugreek seeds (FCE) in breast cancer cells for its estrogenic effect, and to assess its capacity as an alternative to hormone replacement therapy (HRT).. The effect of FCE on cell proliferation of estrogen receptor (ER) positive breast cancer cells, MCF-7 was studied by MTT assay at a concentration range of 20 to 320 microg/ml. The competitive ER binding assay (HAP assay) was done to find out the ER binding capacity of the extract. Transfection and reporter assay (DLR assay), and RT- PCR with an estrogen responsive gene pS2 were done to find out the transcriptional regulatory activity of FCE.. FCE stimulated the proliferation of MCF-7 cells, showed binding to ER (IC(50) = 185.6 +/- 32.8 microg/ ml) and acted as an agonist for ER mediated transcription via ERE. It also induced the expression of estrogen responsive gene pS2 in MCF-7 cells.. Our study provided the evidence for estrogenic activities of fenugreek seeds. Further in vitro and in vivo studies could demonstrate its suitability as an alternative to HRT.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Female; Humans; Phytoestrogens; Plant Extracts; Receptors, Estrogen; Seeds; Trigonella; Tumor Cells, Cultured

In this study, we tested the effects of crude extracts from flax (Linum usitatissimum) on the production of estradiol and expression of estrogen receptor (ER) and progesterone receptor (PR) in human breast cancer MCF7 cells.. Isoflavone and lignan extracts from flax plant Linum usitatissimum were obtained, using different extraction methods. Breast carcinoma cells (MCF7) were incubated with various concentrations of the isolated extracts. Untreated MCF7 cells were used as controls. Supernatants were removed at designated times and tested for estradiol with an ELISA method. Furthermore, the effect of phytoestrogen extracts on the production of ERa and ERbeta as well as on PR was examined.. Production of estradiol is elevated in MCF7 cells in a concentration-dependent manner after stimulation with isoflavone and lignan extracts from Linum usitatissimum. Expression of ERalpha is up-regulated after stimulation with lower concentrations of lignan extracts from flax plants, unchanged at median concentrations and down-regulated at high concentrations. Expression of ERbeta is down-regulated in a concentration-dependent manner.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estradiol; Female; Flax; Gene Expression Regulation, Neoplastic; Humans; Lignans; Phytoestrogens; Plant Extracts; Plant Roots; Receptors, Estrogen; Receptors, Progesterone

Research on the phytoestrogenic effect and its possible mechanism of formononetin.. To evaluate the estrogenic effect and mechanisms of formononetin through the test of its influence on proliferation and ER subtype expression of T47D cells.. The proliferation rates of T47D cells treated with 1 x 10(-7) -1 x 10(-6) mol x L(-1) formononetin were not increased. On the influence of ICI182, 780, the proliferation rates of T47D cells treated with 1 x 10(-7) 1 x 10(-6) mol x L(-1) formononetin were decreased. Formonenetin could induce the augment of ERalpha expression significantly of T47D.. Formonenetin has phytoestrogenic effect Formonenetin can not accelerate ER(+) T47D cell proliferation. But the expression level of ERalpha subtype in T47D cells change significantly with certain concentrations of formonenetin.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Isoflavones; Phytoestrogens; Receptors, Estrogen

To perform an evaluation of selected phytochemicals intake and breast cancer (BC) risk in Mexican women.. We conducted hospital-based case-control study.. Mexico City between 1994 and 1996.. A total of 141 histologically confirmed BC cases were age-matched (+/-3 years) to an equal number of hospital controls. The reproductive history of each woman was obtained by direct interview. The dietary consumption of flavonols, flavones, flavan-3-ols, cinnamic acid, lariciresinol, pinoresinol, secoisolariciresinol, matairesinol and coumestrol was obtained by means of a validated FFQ.. Among postmenopausal women, high dietary intake of flavonols and flavones was associated with a significant reduction of BC risk (high v. low tertile: OR = 0.21, 95 % CI 0.07, 0.60, P for trend = 0.004 and OR = 0.29, 95 % CI 0.10, 0.82, P for trend = 0.025, respectively); consumption of lignans (lariciresinol and pinoresinol) showed a similar effect, but only among premenopausal women (high v. low tertile: OR = 0.32, 95 % CI 0.10, 0.99, P for trend = 0.051 and OR = 0.19, 95 % CI 0.06, 0.62, P for trend = 0.006, respectively).. Our results support a protective role of specific dietary phytochemicals in BC risk by menopausal status, independent of other reproductive factors.

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Diet; Diet Surveys; Feeding Behavior; Female; Flavones; Flavonols; Humans; Lignans; Mexico; Middle Aged; Odds Ratio; Phytoestrogens; Phytosterols; Postmenopause; Premenopause; Risk Factors; Surveys and Questionnaires; Young Adult

Mammographic breast density is an established marker of breast cancer risk, and is hormonally sensitive. Studies suggest that production of the daidzein metabolites equol and O-Desmethylangolensin (ODMA) may be associated with hormones and hormonally mediated factors, but few studies have assessed relationships between the capacity to produce these metabolites and breast density.. To evaluate the relationship between equol- and ODMA-producer phenotypes and breast density in premenopausal women in the United States.. Two hundred and three women attended a clinic visit and 200 provided a urine sample following a 3 day soy challenge. Samples were analyzed for isoflavones by GC-MS to determine daidzein-metabolizing phenotypes. Percent density on recent (<14 month prior to their clinic visit) mammograms was assessed by one reader using a computer-assisted method. Multiple regression analysis was used to assess relationships between the production of equol and ODMA and breast density. Results 55(27.5%) and 182(91%) women were classed as equol- and ODMA-producers (>87.5 ng/ml urine), respectively. In unadjusted and adjusted analyses, there were no differences in breast density between producers and non-producers of either equol or ODMA (P > 0.05).. In this population of low-soy consuming premenopausal women, there were no associations between daidzein-metabolizing phenotypes and breast density, suggesting that these phenotypes per se do not influence premenopausal breast density.

Topics: Adult; Breast; Breast Neoplasms; Equol; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydroxyestrones; Isoflavones; Mammography; Middle Aged; Phenotype; Phytoestrogens; Soy Foods

Breast cancer is a major cause of death worldwide. Amongst the various forms of treatment chemoprevention is favoured and natural products such as the dietary flavonoids have been examined for their cancer preventative activity. In this study we investigated the anticancer activity of the flavonoid diosmetin, as a result of cytochrome P450 CYP1 metabolism. Diosmetin was metabolized to luteolin via an aromatic demethylation reaction on the B-ring from CYP1A1, CYP1B1 and the hepatic isozyme CYP1A2. CYP1A1 and CYP1A2 also produced additional unidentified metabolites. CYP1B1 showed the lowest apparent KM and CYP1A1 the highest apparent Kcat. Diosmetin was also metabolized to luteolin in estrogen receptor positive breast cell-line (MCF-7 cells) preinduced for 24 h with the potent CYP1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Treatment of MCF-7 cells with TCDD caused bioactivation of diosmetin enhancing its cytotoxicity. Taken together these data suggest that the flavonoid diosmetin is metabolised to the more active molecule luteolin by CYP1 family enzymes.

Topics: Aryl Hydrocarbon Hydroxylases; Breast Neoplasms; Cell Proliferation; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System; Flavonoids; Humans; Luteolin; Phytoestrogens; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Phytoestrogens, including miroestrol and deoxymiroestrol, have the ability to act through competition with estrogen for binding to the estrogen receptor (ER). Here, we utilize manual ligand docking followed by molecular dynamics simulations and binding free energy calculations with the linear interaction energy method to predict the binding modes and the binding affinities of phytoestrogens on the ligand binding domain of ER (ERalpha-LBD). The calculations brought about the good correlation between the calculated binding free energy and the bioassays. Furthermore, consideration of Lennard-Jones and Coulomb interaction energies of miroestrol and deoxymiroestrol on ERalpha-LBD provided the information to develop the phytoestrogen derivatives as the preferred drug for ER positive breast cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Breast Neoplasms; Computer Simulation; Coumarins; Drug Discovery; Entropy; Estrogen Receptor alpha; Humans; Models, Chemical; Molecular Structure; Phytoestrogens; Static Electricity; Steroids; Thermodynamics

8-Prenylnaringenin (8PN), one of the strongest plant-derived oestrogen receptors (ERs) ligand, has been suggested to have potential cancer chemo-preventive activities and anti-angiogenic properties. Because published data suggest that ERs serve as nodal point that allows interactions between hormones and growth factors mediated pathways, we decided to investigate the effects exerted by 8PN on Epidermal growth factor (EGF)-elicited pathways in breast cancer cells. Here we show that in ER positive MCF-7 cells, 8PN interferes with EGF induced cell proliferation by strongly inhibiting activation of PI(3)K/Akt pathway, without affecting EGFR expression or tyrosine phosphorylation, and exerting a synergistic activation of Erk1/2 phosphorylation. Moreover, we demonstrate that 8PN is a direct inhibitor of PI(3)K activity as it is shown by in vitro experiments with the purified enzyme and by its inability to impair serine phosphorylation of a constitutive active form of Akt. These findings suggest that inhibition of PI(3)K is a novel mechanism which contributes to 8PN activity to inhibit cancer cell survival and EGF induced proliferation.

Topics: Breast Neoplasms; Cell Line, Tumor; Cyclin D1; Enzyme Activation; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; Female; Flavanones; Humans; Molecular Structure; Phosphatidylinositol 3-Kinases; Phytoestrogens; Receptors, Estrogen; Signal Transduction

Combinations of estrogen receptor agonists have been shown to exert more potent effects than single compounds in many single-endpoint bioassays. However, to our knowledge, it has never been tested how genome-wide expression programs are shaped by the interplay of multiple estrogenic stimuli. In view of the abundance of dietary phytoestrogens, we selected binary mixtures of these phytochemicals to determine their global impact using high-density DNA microarrays. MCF7 cells, a frequent in vitro model for molecular processes associated with breast cancer, were exposed to a sub-saturating concentration of coumestrol either alone or in combination with analogs that exhibit 1000-fold lower estrogen receptor activity. As expected, in the presence of coumestrol, the induction of many estrogen-sensitive genes was not further increased by the addition of resveratrol or enterolactone. However, it was surprising to find that these weak phytoestrogens, when combined with coumestrol in equal concentrations, were able to more than double the number of significantly regulated transcripts. Thus, phytoestrogens with low receptor affinity interact with other estrogenic agonists to generate more widespread expression fingerprints. This effect involving the number of susceptible transcripts instead of their amplitude of induction remains undetected if mixtures are evaluated with conventional bioassays.

Topics: Breast Neoplasms; Cell Survival; Diet; Female; Gene Expression Profiling; Humans; Phytoestrogens; Receptors, Estrogen; Tumor Cells, Cultured

Despite the wide use of Chinese licorice root (Glycyrrhiza uralensis) for the treatment of menopausal complaints, little is known on its potential estrogenic properties, and available information relative to its effects on cell proliferation is contradictory. In this study, the estrogenic properties of licorice root were evaluated in vitro by use of several assays. The effects of increasing concentrations of a DMSO extract of licorice root on the growth of MCF-7 breast cancer cells were biphasic. The extract showed an ER-dependent growth-promoting effect at low concentrations and an ER-independent anti-proliferative activity at high concentrations. In further experiments, licorice root was sequentially extracted to yield four fractions: hexane, EtOAc, methanol and H(2)O. Only the EtOAc extract had effects on cell proliferation similar to the DMSO extract. The hexane extract had no effect on cell growth. In contrast, the methanol and water extracts showed an ER-independent, growth-promoting effect. Similar to its effects on cell proliferation, the EtOAc extract had a biphasic effect on S phase cell cycle distribution and the level of PCNA protein. This extract-induced transactivation of endogenous ERalpha in MCF-7 cells, supported by inducing down-regulation of ERalpha protein and mRNA levels, and up-regulation of ERalpha target genes pS2 and GREB1. These results suggest that the activity of licorice root and the balance between increased risk for cancer and prevention of estrogen-dependent breast cancer may depend on the amount of dietary intake.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Estrogen Replacement Therapy; Estrogens; Female; Glycyrrhiza uralensis; Humans; Phytoestrogens; Plant Extracts; Plant Roots; Proliferating Cell Nuclear Antigen; Solvents

Phytoestrogens (PEs) are non-steroidal ligands, which regulate the expression of number of estrogen receptor-dependent genes responsible for a variety of biological processes. Deciphering the molecular mechanism of action of these compounds is of great importance because it would increase our understanding of the role(s) these bioactive chemicals play in prevention and treatment of estrogen-based diseases. In this study, we applied suppression subtractive hybridization (SSH) to identify genes that are regulated by PEs through either the classic nuclear-based estrogen receptor or membrane-based estrogen receptor pathways. SSH, using mRNA from genistein (GE) treated MCF-7 cells as testers, resulted in a significant increase in GNB1 mRNA expression levels as compared with 10 nM 17beta estradiol or the no treatment control. GNB1 mRNA expression was up regulated two- to fivefold following exposure to 100.0 nM GE. Similarly, GNB1 protein expression was up regulated 12- to 14-fold. GE regulation of GNB1 was estrogen receptor-dependent, in the presence of the anti-estrogen ICI-182,780, both GNB1 mRNA and protein expression were inhibited. Analysis of the GNB1 promoter using ChIP assay showed a PE-dependent association of estrogen receptor alpha (ERalpha) and beta (ERbeta) to the GNB1 promoter. This association was specific for ERalpha since association was not observed when the cells were co-incubated with GE and the ERalpha antagonist, ICI. Our data demonstrate that the levels of G-protein, beta-1 subunit are regulated by PEs through an estrogen receptor pathway and further suggest that PEs may control the ratio of alpha-subunit to beta/gamma-subunits of the G-protein complex in cells. J. Cell. Physiol. 219: 584-594, 2009. (c) 2009 Wiley-Liss, Inc.

Topics: Base Sequence; Binding Sites; Breast Neoplasms; Cell Line, Tumor; DNA Primers; DNA, Neoplasm; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Genistein; GTP-Binding Protein beta Subunits; Humans; Phytoestrogens; Promoter Regions, Genetic; RNA, Messenger; RNA, Neoplasm

We studied the estrogenic activity and cellular effect of wild yam extract in MCF-7 human breast cancer cells. The extract increased the activity of the progesterone receptor and pS2 genes at the mRNA levels in human breast cancer MCF-7 cells, although the effects were not as prominent as those of 17beta-estradiol (E(2)). Western blot analysis showed that the level of estrogen receptor alpha protein was down-regulated after treatment with E(2) or wild yam extract. Wild yam extract also inhibited proliferation of MCF-7 cells. These data indicate that wild yam extract acts as a weak phytoestrogen and protects against proliferation in human breast carcinoma MCF-7 cells.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dioscorea; Estradiol; Estrogen Receptor alpha; Humans; Phytoestrogens; Phytotherapy; Plant Extracts; Presenilin-2; Receptors, Progesterone; RNA, Messenger

It is plausible that polymorphisms in the estrogen receptor alpha and beta genes (ESR1 and ESR2) may modulate the association between enterolactone and breast cancer. Seven polymorphisms in ESR1 (rs827422, rs1709184, rs2347867, rs3020328, rs72207, rs2982896, and rs2234693) and 5 polymorphisms in ESR2 (rs915057, rs1269056, rs1256033, rs3020450, and rs3020443) were selected. The risk of breast cancer for these polymorphisms was estimated among 542 cases and 1076 matched controls from the population-based Malmö Diet and Cancer cohort. The joint effect of these polymorphisms and enterolactone was estimated among those individuals about whom we had information on enterolactone blood concentration (365 cases and 728 controls). Breast cancer risk was not significantly associated with any of the selected polymorphisms. We found a tendency for an interaction between a polymorphism in intron 3 of ESR1 (rs2347867) and enterolactone concentration (P = 0.07). Breast cancer and enterolactone concentration were not associated among those homozygous for the major allele (A) (P = 0.93), whereas we found an inverse association among carriers of the minor allele (G) (P = 0.007). None of the other polymorphisms seem to modify the association between enterolactone and breast cancer. This study suggests that the protective association of enterolactone is reasonably robust across the investigated genotypes. The suggested interaction between enterolactone concentration and rs2347867 needs to be confirmed in larger samples.

Topics: 4-Butyrolactone; Aged; Breast Neoplasms; Cohort Studies; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genetic Predisposition to Disease; Humans; Lignans; Middle Aged; Phytoestrogens; Polymorphism, Single Nucleotide; Prospective Studies

Phytoestrogens are the natural compounds isolated from plants, which are structurally similar to animal estrogen, 17beta-estradiol. Tectoridin, a major isoflavone isolated from the rhizome of Belamcanda chinensis. Tectoridin is known as a phytoestrogen, however, the molecular mechanisms underlying its estrogenic effect are remained unclear. In this study we investigated the estrogenic signaling triggered by tectoridin as compared to a famous phytoestrogen, genistein in MCF-7 human breast cancer cells. Tectoridin scarcely binds to ER alpha as compared to 17beta-estradiol and genistein. Despite poor binding to ER alpha, tectoridin induced potent estrogenic effects, namely recovery of the population of cells in the S-phase after serum starvation, transactivation of the estrogen response element, and induction of MCF-7 cell proliferation. The tectoridin-induced estrogenic effect was severely abrogated by treatment with U0126, a specific MEK1/2 inhibitor. Tectoridin promoted phosphorylation of ERK1/2, but did not affect phosphorylation of ER alpha at Ser(118). It also increased cellular accumulation of cAMP, a hallmark of GPR30-mediated estrogen signaling. These data imply that tectoridin exerts its estrogenic effect mainly via the GPR30 and ERK-mediated rapid nongenomic estrogen signaling pathway. This property of tectoridin sets it aside from genistein where it exerts the estrogenic effects via both an ER-dependent genomic pathway and a GPR30-dependent nongenomic pathway.

Topics: Adenocarcinoma; Breast Neoplasms; Butadienes; Cell Line, Tumor; Cyclic AMP; Drug Interactions; Estradiol; Estrogen Receptor alpha; Female; Genistein; Humans; Isoflavones; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitriles; Phosphorylation; Phytoestrogens; Signal Transduction

The activity of 8-prenylapigenin (8-PA) and its 3'-methoxylated analogue isocannflavin B (IsoB) was investigated in estrogen-dependent T47-D and estrogen-independent MDA-MB-231 human breast cancer cell lines. 8-PA showed a biphasic effect on T47-D cell proliferation, while no significant effect was observed on MDA-MB-231 cells. Conversely, IsoB exhibited only an inhibitory effect on T47-D cell proliferation, accompanied by the appearance of an intense intracytoplasmic vacuolization of autophagic origin. Moreover, biochemical analysis showed that IsoB reduced Akt phosphorylation and p21(Cip1) expression in T47-D cells. These data show that the prenylflavone moiety is a versatile platform for the induction and modulation of bioactivity.

Topics: Antineoplastic Agents, Phytogenic; Autophagy; Breast Neoplasms; Cannabis; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Cytoplasm; Dose-Response Relationship, Drug; Estrogens; Female; Flavanones; Flavones; Flavonoids; Humans; Humulus; Phosphorylation; Phytoestrogens; Phytotherapy; Plant Extracts; Prenylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Vacuoles

Soy food is a rich source of isoflavones--a class of phytoestrogens that has both antiestrogenic and anticarcinogenic properties.. The objective was to evaluate the association of adolescent and adult soy food intake with breast cancer risk in a cohort of 73,223 Chinese women who participated in the Shanghai Women's Health Study.. A validated food-frequency questionnaire was used to assess usual dietary intake during adulthood and adolescence. After a mean follow-up of 7.4 y, 592 incident cases of breast cancer were identified for longitudinal analyses by using Cox regressions.. Adult soy food consumption, measured either by soy protein or isoflavone intake, was inversely associated with the risk of premenopausal breast cancer, and the association was highly statistically significant (P for trend < 0.001). The multivariate-adjusted relative risks (RRs) for the upper intake quintile compared with the lowest quintile were 0.41 (95% CI: 0.25, 0.70) for soy protein intake and 0.44 (95% CI: 0.26, 0.73) for isoflavone intake. High intake of soy foods during adolescence was also associated with a reduced risk of premenopausal breast cancer (RR: 0.57; 95% CI: 0.34, 0.97). Women who consumed a high amount of soy foods consistently during adolescence and adulthood had a substantially reduced risk of breast cancer. No significant association with soy food consumption was found for postmenopausal breast cancer.. This large, population-based, prospective cohort study provides strong evidence of a protective effect of soy food intake against premenopausal breast cancer.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Breast Neoplasms; China; Cohort Studies; Diet Surveys; Female; Glycine max; Humans; Incidence; Isoflavones; Middle Aged; Phytoestrogens; Premenopause; Proportional Hazards Models; Risk Factors; Soy Foods; Soybean Proteins

The reduced incidence of breast cancer in certain Eastern countries has been attributed to high soy diets although this evidence is simply epidemiological. One of the major constituents of soy is genistein, but paradoxically this phytoestrogen binds to oestrogen receptors and stimulates growth at concentrations that would be achieved by a high soy diet, but inhibits growth at high experimental concentrations. To determine the effects of low-dose, long-term genistein exposure we have cultured MCF-7 breast cancer cells in 10 nM genistein for 10-12 weeks and investigated whether or not this long-term genistein treatment (LTGT) altered the expression of oestrogen receptor alpha (ERalpha) and the activity of the PI3-K/Akt signalling pathway. This is known to be pivotal in the signalling of mitogens such as oestradiol (E(2)), insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). LTGT significantly reduced the growth promoting effects of E(2) and increased the dose-dependent growth-inhibitory effect of the PI3-K inhibitor, LY 294002, compared to untreated control MCF-7 cells. This was associated with a significant decreased protein expression of total Akt and phosphorylated Akt but not ERalpha. Rapamycin, an inhibitor of one of the down-stream targets of Akt, mammalian target of rapamycin (mTOR), also dose-dependently inhibited growth but the response to this drug was similar in LTGT and control MCF-7 cells. The protein expression of liver receptor homologue-1 (LRH1), an orphan nuclear receptor implicated in tumourigenesis was not affected by LTGT. The results show that LTGT results in a down-regulation of the PI3-K/Akt signalling pathway and may be a mechanism through which genistein could offer protection against breast cancer.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Estradiol; Estrogen Antagonists; Female; Genistein; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phytoestrogens; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction

Genistein, a soy component, has been shown to have a biphasic proliferative effect in breast cancer cells, inhibiting in vitro cell proliferation at high concentrations (>10 micromol/l), while stimulating cell proliferation at lower concentrations (<10 micromol/l). However, epidemiological studies have shown an inverse correlation between the intake of genistein and the incidence of breast cancer. One of the possible reasons for this discrepancy could be the differing status of the estrogen receptor (ERalpha and/or ERbeta). Genistein selectively binds to ERbeta with strong affinity and thereby could be a potential chemotherapeutic agent against breast cancer of the ERalpha-negative and ERbeta-positive type. Therefore, the objective of the present study was to determine whether the proliferative effects of genistein were caused by its activity as a selective ERbeta agonist or merely as an antiestrogen.. This study was carried out in MDA-MB-231 (ERbeta) and T47D (ERalpha and ERbeta) human breast cancer cells. Cell proliferation was determined by the MTT (3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide) assay. The cells were grown in estrogen-starved media and exposed to genistein at different concentrations for 72 h, either in the presence or absence of 17beta-estradiol.. A significant decrease in cell proliferation was seen in MDA-MB-231 cells at low concentrations of genistein in the presence of 17beta-estradiol, as compared to genistein alone. In T47D cells, which are known to have a predominance of ERalpha over ERbeta, genistein showed a biphasic cell proliferative response both in the presence and absence of 17beta-estradiol.. Our results suggest that in cells with a predominance of ERalpha, genistein acts as an agonist to ERalpha, and in cells with ERbeta alone, genistein most likely acts as an antiestrogen. Our results also suggest that genistein could be useful as a chemotherapeutic agent in premenopausal women with breast cancer of the ERalpha-negative and ERbeta-positive type.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genistein; Humans; Phytoestrogens

A novel, selective and sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for the simultaneous determination of phytoestrogens and their key metabolites in human urine in this study. This method includes internal standard (IS) screening, analytical sample preparation procedure establishment, and linear range investigation. The analytical sample was extracted by liquid-liquid extraction from urine sample. The phytoestrogens and related key metabolites were separated with Agilent Zorbax Eclipse XDB-C18 chromatographic column using methanol and water as mobile phase. The Quattro premier MICROMASS mass spectrometer in negative ion selected reaction monitoring (SRM) mode using electrospray ionization was applied to detect the phytoestrogens and key metabolites. To validate the developed liquid chromatography-tandem mass spectrometry method, the intra- and inter-day precisions, specificity, sensitivity, reproducibility, and sample detective concentration range were evaluated. This is the first reported phytoestrogens analysis and validation study that demonstrates the feasibility of using liquid chromatography-electrospray ionization mass spectrometry to simultaneously analyze ten analytes including both phytoestrogens and their key metabolites in urine samples collected for epidemiological studies in human.

Topics: Breast Neoplasms; Calibration; Case-Control Studies; Chemistry, Pharmaceutical; Chromatography; Chromatography, Liquid; Female; Humans; Methanol; Models, Chemical; Phytoestrogens; Quality Control; Reproducibility of Results; Tandem Mass Spectrometry; Time Factors; Water

The objective of this study was to examine the association of urinary phytoestrogens with the risk of postmenopausal breast cancer. Participants in the Multiethnic Cohort Study included 36,458 postmenopausal women who provided blood or urine specimens. A nested case-control study of breast cancer with biospecimens was created in which cases diagnosed after specimen collection were matched to two controls. Two hundred fifty-one women with breast cancer and 462 controls had urine available for analysis of urinary phytoestrogens. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using conditional logistic regression. A nonmonotonic inverse trend (P = 0.04) in breast cancer risk was associated with increasing urinary excretion of genistein (OR 25th-75th percentile, 0.88; 95% CI, 0.78-0.99) and total isoflavones (OR 25th-75th percentile, 0.80; 95% CI, 0.65-0.99). A significant reduction in breast cancer risk in Japanese-American women was associated with the highest compared with the lowest quartile excretion of urinary daidzein (OR, 0.41; 95% CI, 0.19-0.89; P(trend), 0.005). The risk of breast cancer was reduced among White women with the highest compared with the lowest quartile excretion of equol (OR, 0.27; 95% CI, 0.08-0.95), although the trend in risk was not significant (P = 0.07). Our results provide some support to the hypothesis that a diet rich in isoflavones from soy products reduces the risk of postmenopausal breast cancer, particularly in populations with comparatively high excretion of phytoestrogens.

Topics: Aged; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Cohort Studies; Ethnicity; Female; Humans; Phytoestrogens; Postmenopause; Risk Factors

The effect of macelignan, a phytoestrogen, on P-gp function was investigated using multidrug resistant cancer cells overexpressing P-gp (NCI/ADR-RES) and the fluorescent P-gp substrates, daunorubicin and rhodamine 123. Macelignan (40 microM) increased the cellular accumulation of daunorubicin by approximately threefold in NCI/ADR-RES cells, whereas it did not alter the cellular accumulation of daunorubicin in MCF-7/sensitive cells. Similarly, the presence of macelignan also enhanced significantly (P < 0.05) the cellular accumulation of rhodamine 123 in a concentration-dependent manner in NCI/ADR-RES cells. Furthermore, cancer cells were more susceptible to the cytotoxicity of vinblastine, a P-gp substrate, in the presence of macelignan. Those results suggest that macelignan has inhibitory effects on P-gp mediated cellular efflux. However, P-gp activity did not affect the cellular accumulation of macelignan itself. Taken all together, macelignan was identified as a novel inhibitor of P-gp activity and may be a promising lead compound for the rational design of more efficacious drugs to reverse multidrug resistance in cancer.

Topics: Adenocarcinoma; Analysis of Variance; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B; Biological Transport, Active; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Daunorubicin; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluorescent Dyes; Growth Inhibitors; Humans; Lignans; Phytoestrogens; Phytotherapy; Rhodamine 123; Vinblastine

To observe the effects of Astragalus injection, astragaloside IV and formononetin on proliferation and Akt phosphorylation of basal-like human breast carcinoma cell lines MDA-MB-468 and MDA-MB-231.. The effects of different concentrations of Astragalus injection, astragaloside IV and formononetin on proliferation of breast cancer cell lines were assayed by methyl thiazolyl tetrazolium (MTT) assay, and their effects on phospho-Akt were assayed by in-cell Western blot method.. The results of the MTT assay showed that the best concentrations of Astragalus injection, astragaloside IV, formononetin and astragaloside IV plus formononetin were 1 g/mL, 80 microg/mL, 40 microg/mL and 10 microg/mL plus 40 microg/mL respectively. After 1- or 2-day culture, Astragalus injection, astragaloside IV, formononetin and astragaloside IV plus formononetin decreased the expressions of p-Akt (Thr 308) and p-Akt (Ser 473) in MDA-MB-468 cells. Formononetin and astragaloside IV plus formononetin down-regulated the expression of p-Akt (Thr 308) protein in MDA-MB-231 cells after 1- and 2-day culture, but had no effects on the expression of p-Akt (Ser 473) protein in MDA-MB-231 cells.. Astragalus injection, astragaloside IV and formononetin can inhibit proliferation of breast cancer cell lines MDA-MB-468 and MDA-MB-231, and the antiproliferation effects vary according to their concentrations. And the antiproliferation mechanisms may be related to their down-regulation effects on Akt phosphorylation.

Topics: Apoptosis; Astragalus Plant; Breast Neoplasms; Cell Proliferation; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Oncogene Protein v-akt; Phosphorylation; Phytoestrogens; Saponins; Triterpenes

Topics: Breast Neoplasms; Estrogen Replacement Therapy; Female; Humans; Phytoestrogens; Plant Preparations; Risk Factors; Women's Health

There is a large variation in breast cancer incidence and mortality rates worldwide. Migration studies have indicated that this variation is primarily the result of lifestyle influences. Although there has been much research conducted, definitively identifying dietary factors that impact breast cancer risk has proven difficult. In part this may be because most clinical and epidemiologic studies have focused on adult dietary exposure. However, evidence suggests that childhood and/or adolescence is the period of life when the breast is most sensitive to dietary influences. Further, the available epidemiologic and animal data suggest that early soy intake reduces breast cancer risk. Soy foods are unique dietary sources of isoflavones, diphenolic compounds that exert estrogen-like effects under certain experimental conditions. The protection effects of soy may result from the soybean isoflavones stimulating differentiation of the breast in much the same way that the elevated estrogen levels do during pregnancy. More specifically, in rats, the primary isoflavone genistein reduces mammary tumorigenesis and increases mammary tissue differentiation by leading to a reduction in the number of terminal end buds (TEB) and an increase in the number of differentiated lobules. There is need and justification for continued investigation of the early soy intake hypothesis, particularly to determine the cellular targets of soy action and to identify the signaling pathways mediating the effects on mammary gland morphology and susceptibility to breast cancer.

Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; Adult; Aging; Animals; Anticarcinogenic Agents; Breast; Breast Neoplasms; Child; Child Nutritional Physiological Phenomena; Diet; Female; Genistein; Glycine max; Humans; Isoflavones; Mammary Neoplasms, Experimental; Maternal Nutritional Physiological Phenomena; Mice; Phytoestrogens; Pregnancy; Rats; Risk; Soy Foods

Topics: Breast Neoplasms; Climacteric; Complementary Therapies; Coronary Artery Disease; Female; Hormone Replacement Therapy; Hot Flashes; Humans; Life Style; Osteoporosis, Postmenopausal; Phytoestrogens; Risk Factors; Thrombosis

Pueraria mirifica and its extracts are widely used as the ingredient(s) in many rejuvenating products. Up to now, the extract of P. mirifica roots that has been used in most studies, is the alcoholic extract. In the present study, we investigated the estrogenic activity using uterotropic and MCF-7 cell proliferation models of the dichloromethane extract as well as the water extract which was obtained from partitioning the ethanolic extract. The results indicated that among the three extracts, i.e. the ethanolic extract (PM1), the water extract (PM2) and dichloromethane extract (PM3), PM3 exhibited the most potent estrogenic activity in both models, followed by PM1. The extracts produced uterotropic activity associated with the increase of water content while uterotropic activity of 17beta-estradiol was related to the increase of muscle mass. The two isoflavonoids, genistein and daidzein, were not the major active phytoestrogens involving the estrogenic activity of these extracts.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Female; Humans; Ovary; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Roots; Pueraria; Rats; Rats, Wistar; Uterus

The risks and benefits of diets and supplements containing the estrogenic soy isoflavone genistein are not well established. We report that 10 nm genistein potently induces the granzyme B inhibitor, proteinase inhibitor 9 (PI-9) in MCF-7 human breast cancer cells. By inducing PI-9, genistein inhibits the ability of human natural killer (NK) cells to lyse the target breast cancer cells. In ERalphaHA cells, stably transfected MCF-7 cells, which contain elevated levels of estrogen receptor-alpha (ERalpha), 100 pm genistein or 17beta-estradiol potently induce PI-9 and prevent NK cells from killing the target breast cancer cells. The concentrations of genistein that fully induce PI-9 in MCF-7 cells, and in ERalphaHA cells, are far lower than those previously reported to elicit estrogenic responses through ERalpha. Because 4-hydroxytamoxifen, raloxifene, and ICI 182,780/Faslodex all block genistein induction of PI-9 and elevated levels of ERalpha enhance induction of PI-9, genistein acts via ERalpha to induce PI-9. Increasing levels of ERalpha in breast cancer cells results in a progressive increase in induction of PI-9 by genistein and in the cell's ability to evade killing by NK cells. Moderate levels of dietary genistein and soy flour effectively induce PI-9 in human breast cancers grown in ovariectomized athymic mice. A significant population consumes levels of genistein in soy products that may be high enough to induce PI-9, perhaps potentiating the survival of some preexisting breast cancers by enabling them to evade immunosurveillance.

Topics: Animals; Breast Neoplasms; Cell Death; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Genistein; Glycine max; Humans; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Mice, Nude; Phytoestrogens; Serpins; Tumor Cells, Cultured; Tumor Escape; Xenograft Model Antitumor Assays

Topics: Breast Neoplasms; Dietary Supplements; Female; Humans; Phytoestrogens; Risk Factors; Surveys and Questionnaires

This study investigates the importance of the intracellular ratio of the two estrogen receptors ERalpha and ERbeta for the ultimate potential of the phytoestrogens genistein and quercetin to stimulate or inhibit cancer cell proliferation. This is of importance because (i) ERbeta has been postulated to play a role in modulating ERalpha-mediated cell proliferation, (ii) genistein and quercetin may be agonists for both receptor types and (iii) the ratio of ERalpha to ERbeta is known to vary between tissues. Using human osteosarcoma (U2OS) ERalpha or ERbeta reporter cells it was shown that compared to estradiol (E2), genistein and quercetin have not only a relatively greater preference for ERbeta but also a higher maximal potential for activating ERbeta-mediated gene expression. Using the human T47D breast cancer cell line with tetracycline-dependent ERbeta expression (T47D-ERbeta), the effect of a varying intracellular ERalpha/ERbeta ratio on E2- or pythoestrogen-induced cell proliferation was characterised. E2-induced proliferation of cells in which ERbeta expression was inhibited was similar to that of the T47D wild type cells, whereas this E2-induced cell proliferation was no longer observed when ERbeta expression was increased. With increased expression of ERbeta the phytoestrogen-induced cell proliferation was also reduced. These results point at the importance of the cellular ERalpha/ERbeta ratio for the ultimate effect of (phyto)estrogens on cell proliferation.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Genistein; Humans; Phytoestrogens; Quercetin; Tetracycline

Biochanin A is an isoflavone isolated from red clover (Trifolium pratense), and is a commercially available nutraceutical for women suffering from postmenopausal symptoms. Isoflavones resemble the structure of oestrogen, and display agonistic and antagonistic interactions with the oestrogen receptor. Overexposure of oestrogen is a major contributing factor in the development of breast cancer, and cytochrome P450 (CYP) 19 enzyme, or aromatase, catalyses the reaction converting androgen to oestrogen. In the present study the effect of biochanin A on the gene regulation and enzyme activity of aromatase was investigated. By assaying MCF-7 cells stably transfected with CYP19, biochanin A inhibited aromatase activity and hampered cell growth attributing to the enzyme activity. In addition, 25 microm-biochanin A significantly reduced CYP19 mRNA abundance in the oestrogen receptor-negative breast cancer cells SK-BR-3. The transcriptional control of the CYP19 gene is exon-specific, and promoter regions I.3 and II have been shown to be responsible for CYP19 expression in SK-BR-3 cells. Luciferase reporter gene assays also revealed that biochanin A could repress the transcriptional control dictated by the promoter regulation. Interestingly, genistein did not inhibit aromatase but it might down regulate promoter I.3 and II transactivation. Since genistein is a major metabolite of biochanin A, it might contribute to biochanin A's suppressive effect on CYP19 expression. The present study illustrated that biochanin A inhibited CYP19 activity and gene expression.

Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Division; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Genistein; Humans; Phytoestrogens; Promoter Regions, Genetic; RNA, Messenger; Transcriptional Activation; Trifolium; Tumor Cells, Cultured

Ginsenoside Rg1, an active ingredient commonly found in ginseng root, was previously demonstrated to be a phytoestrogen that exerted estrogen-like activity without direct interaction with estrogen receptors (ERs) in human breast cancer (MCF-7) cells. The present study was designed to determine the molecular mechanism by which Rg1 exerted estrogenic effects. Co-incubation of MCF-7 cells with 1 microM of ER antagonist ICI182780 abolished the inductive effects of Rg1 on pS2 expression as well as ERE-luciferase activity, suggesting that the estrogenic effects of Rg1 were mediated through the endogenous ERs. To evaluate the relative involvement of ERalpha and ERbeta in mediating the actions of Rg1, ER-negative human embryonic kidney (HEK293) cells were co-transfected with the ERE-luciferase reporter construct and either ERalpha or ERbeta construct. The results showed that Rg1 could activate ERE-luciferase activity via the ERalpha-mediated pathway in a dose-dependent manner (10(-14) to 10(-6)M); whereas, the activation of ERbeta-mediated ERE-luciferase activity by Rg1 only occur at high concentration (10(-6)M). Furthermore, the results showed that 1pM Rg1 could rapidly induce phosphorylation of the AF-1 domain of ERalpha at serine 118 residue within the first 5 min of incubation, suggesting that Rg1 activates ERalpha in a ligand-independent manner. Taken together, our results indicate that Rg1 preferentially activates ERalpha via phosphorylation of AF-1 domain in the absence of receptor binding. This study is the first to provide evidence that ginsenoside Rg1 exerts estrogen-like actions via ligand-independent activation of ERalpha pathway.

Topics: Breast Neoplasms; Cells, Cultured; Drug Evaluation, Preclinical; Estradiol; Estrogen Receptor alpha; Fulvestrant; Gene Expression Regulation; Genes, Reporter; Ginsenosides; Humans; Insulin-Like Growth Factor I; Ligands; Luciferases; Phosphorylation; Phytoestrogens; RNA, Messenger; Signal Transduction; Transfection

To evaluate whether phytoestrogen intake is associated with reduced breast cancer risk, using a novel phytoestrogen database.. Population-based breast cancer cases aged 25-74 years (diagnosed 2002-2003) were identified using Ontario Cancer Registry (n = 3,063) and controls (n = 3,430) were an age-stratified random sample of women identified through random digit dialing. An epidemiologic and Block food frequency questionnaire--expanded to include phytoestrogen-containing foods--was mailed to all subjects. The recently published Ontario phytoestrogen database was applied to FFQ responses to estimate intake. Multivariate logistic regression provided odds ratio (OR) estimates, while controlling for confounders.. Among all women, lignan intake was associated with a reduced breast cancer risk (Q5 vs. Q1 MVOR: 0.81, 95% CI: 0.65, 0.99); however, following stratification by BMI, this reduction in risk was statistically significant only among overweight (BMI > 25) women. Total phytoestrogen intake was also associated with a risk reduction among overweight women only. Among pre-menopausal women, total phytoestrogen intake was associated with a significant reduction in breast cancer risk among overweight women only (Q5 vs. Q1 MVOR: 0.51, 95% CI: 0.30, 0.87). Among post-menopausal women, no statistically significant association was observed between breast cancer risk and isoflavones or lignans.. Lignan intake may be associated with reduced breast cancer risk among pre-menopausal women, and our data suggest BMI modifies this association.

Topics: Adult; Aged; Body Mass Index; Breast Neoplasms; Canada; Case-Control Studies; Diet; Diet Surveys; Female; Humans; Isoflavones; Lignans; Middle Aged; Phytoestrogens; Postmenopause; Premenopause; Risk Factors; Surveys and Questionnaires

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Female; Glycine max; Humans; Infant; Infant Formula; Infant, Newborn; Middle Aged; Nutrition Surveys; Odds Ratio; Phytoestrogens; Risk Factors

Five new dibenzylbutane type lignans (1-5) were isolated from the stem bark of Iryanthera lancifolia. Their structures were determined by extensive 1D and 2D NMR spectroscopic studies and chemical evidence. Seventeen of the isolated compounds were tested for their estrogenic activities in the estrogen responsive human breast cancer cell line MCF-7 BUS using the E-Screen proliferation assay. Cell proliferation was evaluated by the SRB assay to calculate the estrogenic parameters. The majority of the compounds induced a mitogenic response. This effect, given as Relative Proliferative Effect (RPE) to reference estrogen 17beta-estradiol (E(2)), ranged between 14% and 84%.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Lignans; Molecular Structure; Phytoestrogens

Topics: Breast Neoplasms; Female; Humans; Isoflavones; Phytoestrogens; Risk Factors

Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogen-regulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor alpha (ERalpha); these cell lines stably express estrogen response element (beta-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dose-dependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1-10 microM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERalpha-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, gamma-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.

Topics: Breast Neoplasms; Cell Survival; Estrogen Receptor alpha; Estrogens; Female; Genistein; Humans; Phosphotransferases; Phytoestrogens; Up-Regulation; Vascular Endothelial Growth Factor A; Xenobiotics

The nutritional intake of phytoestrogens seems to reduce the risk of breast cancer or other neoplastic diseases. However, these epidemiological findings remain controversial because low doses of phytoestrogens, achievable through soy-rich diets, stimulate the proliferation of estrogen-sensitive tumor cells. The question of whether such phytochemicals prevent cancer or rather pose additional health hazards prompted us to examine global gene expression programs induced by a typical soy product. After extraction from soymilk, phytoestrogens were deconjugated and processed through reverse- and normal-phase cartridges. The resulting mixture was used to treat human target cells that represent a common model system for mammary tumorigenesis. Analysis of mRNA on high-density microarrays revealed that soy phytoestrogens induce a genomic fingerprint that is indistinguishable from the transcriptional effects of the endogenous hormone 17beta-estradiol. Highly congruent responses were also observed by comparing the physiologic estradiol with daidzein, coumestrol, enterolactone, or resveratrol, each representing distinct phytoestrogen structures. More diverging transcriptional profiles were generated when an inducible promoter was used to reconstitute the expression of estrogen receptor beta (ERbeta). Therefore, phytoestrogens appear to mitigate estrogenic signaling in the presence of both ER subtypes but, in late-stage cancer cells lacking ERbeta, these phytochemicals contribute to a tumor-promoting transcriptional signature.

Topics: 4-Butyrolactone; Animals; Biomarkers, Tumor; Breast Neoplasms; Cattle; Estradiol; Estrogen Receptor beta; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genistein; Humans; Isoflavones; Lignans; Milk; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Phytoestrogens; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Soy Milk; Tumor Cells, Cultured

There is evidence that metabolic activation can increase the estrogenic activity of the phytoestrogen-rich herb in tests with HepG2 cells. Variation in both plant genetics and harvest season may also influence estrogenic activity of the plant materials. We evaluated the influence of in vitro metabolic activation by S9 mixture on the estrogenic activity of tuberous samples of different cultivars of the phytoestrogen-rich herb, Pueraria mirifica, harvested in different seasons.. Plant extracts were derived from the tubers of five plant cultivars collected during summer, rainy season and winter and administered to MCF-7 cultures, an ERalpha-positive human mammary adenocarcinoma cell line for 3 days at dosages of 0.1, 1, 10, 100 and 1000microg/ml. These data were compared with the major plant isoflavonoids puerarin, daidzin, genistin, daidzein and genistein and with 17beta-estradiol, at concentrations of 10(-12) to 10(-6)M. The test system was done in the absence and presence of the S9 mixture.. The major plant isoflavonoids and the plant extracts exhibited variable degrees of estrogenic activities as evaluated by altered proliferation of the MCF-7 cell line which were significantly enhanced in the presence of the S9 mixture.. Metabolic activation of plant isoflavonoids at least in vitro by S9 mixture plays a significant role in amplification of the estrogenic activity of the phytoestrogen-rich plant. In addition, the estrogenic activities of the plant samples were potentially influenced by both seasonal changes and plant genetics.

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Plant Extracts; Pueraria; Seasons

Phytoestrogens are a group of compounds found in plants that structurally resemble the hormone oestradiol, and thus have the potential to act as oestrogen agonists or antagonists. Their potential effects may alter the risk of breast cancer, but only a limited range of phytoestrogens has been examined in prospective cohort studies.. Serum and urine samples from 237 incident breast cancer cases and 952 control individuals (aged 45 to 75 years) in the European Prospective into Cancer-Norfolk cohort were analysed for seven phytoestrogens (daidzein, enterodiol, enterolactone, genistein, glycitein, o-desmethylangolensin, and equol) using liquid chromatography/mass spectrometry. Data on participants' diet, demographics, anthropometrics, and medical history were collected upon recruitment. All models were adjusted for weight, fat and energy intake, family history of breast cancer, social class, analytical batch, and factors related to oestrogen exposure.. Urinary or serum phytoestrogens were not associated with protection from breast cancer in the European Prospective into Cancer-Norfolk cohort. Breast cancer risk was marginally increased with higher levels of total urinary isoflavones (odds ratio = 1.08 (95% confidence interval = 1.00 to 1.16), P = 0.055); among those with oestrogen receptor-positive tumours, the risk of breast cancer was increased with higher levels of urinary equol (odds ratio = 1.07 (95% confidence interval = 1.01 to 1.12), P = 0.013).. There was limited evidence of an association between phytoestrogen biomarkers and breast cancer risk in the present study. There was no indication of decreased likelihood of breast cancer with higher levels of phytoestrogen biomarkers, but the observation that some phytoestrogen biomarkers may be associated with greater risk of breast cancer warrants further study with greater statistical power.

Topics: Aged; Biomarkers, Tumor; Breast Neoplasms; Cohort Studies; Female; Health Status; Humans; Life Style; Middle Aged; Phytoestrogens; Prospective Studies; Risk Assessment; Risk Factors; Surveys and Questionnaires

Results from epidemiological and experimental studies indicate that phytoestrogens may protect against breast cancer. Because one of the biological effects of phytoestrogens is probably estrogenic, it's possible that the preventive effect on breast cancer differs by estrogen receptor (ER) or progesterone receptor (PR) status of the tumor. We evaluated the associations between dietary phytoestrogen (isoflavonoids, lignans, and coumestrol) intake and risk of breast cancer and whether the ER/PR statuses of the tumor influence this relationship. In 1991-2 a prospective population-based cohort study among Swedish pre- and postmenopausal women was performed, making questionnaire data available for 45,448 women. A total of 1014 invasive breast cancers were diagnosed until December 2004. Cox proportional hazards models were performed to estimate multivariate risk ratios, 95% CI for associations with risk of breast cancer. Intakes of lignan, isoflavonoid, or coumestrol were not associated with breast cancer risk overall or before or after 50 y of age. The effects of lignans or isoflavonoids were independent of receptor status. However, intake of coumestrol was associated with decreased risk of receptor negative tumors (ER-PR-) but not positive tumors. The risk of ER-PR- tumors was significantly lower (50%) in women with intermediate coumestrol intake compared with those who did not consume any. In conclusion, we found no association between intake of isoflavonoids or lignans and breast cancer risk. Our results of a decreased risk of ER-PR- tumors in women with intermediate intake of coumestrol could be due to chance because of the low intake. The results should be confirmed in other studies.

Topics: Adult; Breast Neoplasms; Cohort Studies; Coumestrol; Diet; Dietary Fiber; Female; Flavonoids; Humans; Lignans; Middle Aged; Phytoestrogens; Prospective Studies; Receptors, Estrogen; Receptors, Progesterone; Risk Factors; Surveys and Questionnaires; Sweden

The soyabean isoflavones genistein and daidzein, which may protect against some cancers, cardiovascular disease and bone mineral loss, undergo substantial Phase 2 metabolism, predominantly glucuronidation. We observed a correlation between rates of metabolism of marker substrates of specific UGTs and rates of glucuronidation of genistein and daidzein in vitro by a panel of human liver microsomes, demonstrating that UGT1A1 and UGT1A9, but not UGT1A4, make a major contribution to the metabolism of these isoflavones by human liver. These findings were substantiated by observations that recombinant human UGT1A1 and UGT1A9, but not UGT1A4, catalysed the production of the major glucuronides of both genistein and daidzein in vitro. Recombinant human UGT1A8 also metabolised both genistein and daidzein, whereas UGT1A6 was specific to genistein and UGTs 2B7 and 2B15 were inactive, or only marginally active, with either isoflavone as substrate. The intestinal isoform UGT1A10 metabolised either both isoflavones or genistein only, depending on the commercial supplier of the recombinant enzyme, possibly as a result of a difference in amino acid sequence, which we were unable to confirm. Daidzein (16 microM) increased cell death in the MCF-7 human breast cancer cell line and this effect was reversed by glucuronidation. In view of a well-characterised functional polymorphism in UGT1A1, these observations may have implications for inter-individual variability in the potential health-beneficial effects of isoflavone consumption.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Line, Tumor; Chromatography, High Pressure Liquid; Genistein; Glucuronides; Glucuronosyltransferase; Glycine max; Humans; Isoflavones; Liver; Models, Chemical; Phytoestrogens; UDP-Glucuronosyltransferase 1A9

Lignans are plant compounds metabolized in the mammalian gut to produce the estrogenic enterolignans, enterodiol (ED) and enterolactone (EL). Because estrogens have been linked to breast cancer etiology, enterolignans could affect breast cancer risk, but to our knowledge, the mechanisms by which they exert their estrogenic and/or anti-estrogenic effects in humans are still unclear. To better understand how estrogenic compounds from the food, such as the enterolignans, might influence breast cancer progression and their mechanisms to interfere with human estrogen receptor (ER) signalling in hormone-dependant diseases, we examined and compared the ability of ED, EL and 17beta-estradiol (E2) to induce the transactivation of ERalpha and ERbeta, to modulate ERalpha target genes, to exert either growth stimulatory or anti-proliferative effects and finally to modulate MCF-7 cell migration by acting on matrix metalloproteases (MMP)-2 and -9, at concentrations that are achievable through a lignan-rich diet. This study indicates that enterolignans show distinct properties for transactivation of ERalpha and ERbeta. ED, as E2, induces ERalpha transcriptional activation through transactivation functions AF-1 and AF-2, while EL is less efficient in inducing AF-1, acting predominantly through AF-2. Furthermore, ED and EL modulate ERalpha mRNA and protein contents as well as MCF-7 cell proliferation and secreted MMP activities in a different way. Enterolignans are compounds of wide interest nowadays and our results help to unveil their mechanisms of action on ER, emphasizing the fact that the dietary load in lignans could be of importance in the balance between being risk or chemopreventive factors for breast cancer and women's health.

Topics: 4-Butyrolactone; Animals; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; Estrogen Receptor alpha; Flavonoids; HeLa Cells; Humans; Lignans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phenols; Phytoestrogens; Polyphenols; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation

The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4'- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [(3)H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4'-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4'-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Equol; Estradiol; Estrogen Receptor alpha; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Recombinant Proteins; Structure-Activity Relationship; Sulfates

The activation of 17beta-estradiol (E2) to 2-hydroxyestradiol (2-HO-E2), the more genotoxic 4-hydroxyestradiol (4-HO-E2), and the oxidation to the respective quinones constitutes a risk factor in hormonal carcinogenesis. 2-HO-E2 is formed by cytochrome P450 CYP1A1, and 4-HO-E2 is formed by CYP1B1. Both are detoxified by catechol-O-methyltransferase (COMT), whereas their quinones are inactivated by NADPH-quinone-oxidoreductase (QR). Since the soy isoflavones genistein (GEN) and daidzein (DAI) are widely consumed due to their putative protective function in breast carcinogenesis, we examined the influence of E2, GEN, and DAI on CYP1A1/1B1, COMT, and QR expression in MCF-7 cells by reverse transcription/competitive PCR. CYP1A1 and COMT enzyme activity were determined using ethoxyresorufin and quercetin as substrates. Furthermore, estrogen receptor (ER)-regulated cell proliferation was determined by E-screen. E2, GEN, and DAI inhibited the expression of CYP1A1, COMT, and QR. The maximum effect (reduction by 40-80%, depending on the gene product and compound) was obtained at 100 pM E2, 1 microM GEN, and 10 microM DAI, which also induced the most pronounced cell proliferation in the E-screen. In contrast, expression of CYP1B1 was only slightly affected. CYP1A1 and COMT mRNA levels correlated with enzyme activities. The ER antagonist ICI 182,780 reversed the E2- and isoflavone-mediated effects. Thus, GEN and DAI at estrogen-active concentrations stimulate the formation of the more E2 genotoxic metabolites and inhibit the detoxification of catechol and quinone estrogens in estrogen-responsive tumor cells.

Topics: Aryl Hydrocarbon Hydroxylases; Breast Neoplasms; Catechol O-Methyltransferase; Cell Proliferation; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Estradiol; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genistein; Humans; Isoflavones; NAD(P)H Dehydrogenase (Quinone); Phytoestrogens; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Epidemiological evidence suggests that carotenoids prevent several types of cancer, including mammary and endometrial cancers. On the other hand, such studies have also shown that estrogens are the most important risk factors for these cancer types. Genistein, the phytoestrogen mainly found in soy, also shows significant estrogenic activity when tested at concentrations found in human blood. The aim of this study was to determine whether carotenoids inhibit signaling of steroidal estrogen and phytoestrogen which could explain their cancer preventive activity. Similar to the known effect of 17beta-estradiol (E(2)), treatment of breast (T47D and MCF-7) and endometrial (ECC-1) cancer cells with phytoestrogens induced cell proliferation, cell-cycle progression and transactivation of the estrogen response element (ERE). However, each of the tested carotenoids (lycopene, phytoene, phytofluene, and beta-carotene) inhibited cancer cell proliferation induced by either E(2) or genistein. The inhibition of cell growth by lycopene was accompanied by slow down of cell-cycle progression from G1 to S phase. Moreover, the carotenoids inhibited estrogen-induced transactivation of ERE that was mediated by both estrogen receptors (ERs) ERalpha and ERbeta. The possibility that this inhibition results from competition of carotenoid-activated transcription systems on a limited pool of shared coactivators with the ERE transcription system was tested. Although cotransfection of breast and endometrial cancer cells with four different coactivators (SRC-1, SRC-2, SRC-3, and DRIP) strongly stimulated ERE reporter gene activity, it did not oppose the inhibitory effect of carotenoids. These results suggest that dietary carotenoids inhibit estrogen signaling of both 17beta-estradiol and genistein, and attenuate their deleterious effect in hormone-dependent malignancies.

Topics: Breast Neoplasms; Carotenoids; Cell Cycle; Cell Proliferation; Estrogen Antagonists; Estrone; Female; Genistein; Humans; Lycopene; Phytoestrogens; Receptors, Estrogen; Receptors, Progesterone; Response Elements; Transcription, Genetic; Tumor Cells, Cultured

A protective effect of plant extract from Onobrychis ebenoides on ovariectomy-induced bone loss in rats has been shown. To investigate the molecular mechanisms that underly the beneficial effect of O. ebenoides (Onb) on bone loss, we studied its potential to activate ER subtypes (ERalpha and ERbeta) on transiently transfected HeLa cells with HO-hERalpha or pSG5-hERbeta and 3xERE-TATA-Luc expression vectors. Its impact to stimulate differentiation and mineralization of osteoblasts (KS483 cell line) by Alizarin Red-S staining was also examined. Furthermore we sought to induce for its potential the IGFBP3, a known estrogen-dependent marker in MCF7 breast cancer cells. 17beta-Estradiol and the pure antiestrogen ICI182780 were included to serve as control samples of the estrogenic and antiestrogenic activity respectively. Our data revealed: (1) Onb extract displayed a significant estrogenic activity on both ERalpha and ERbeta subtypes. (2) It exhibited direct action on osteoblasts by inducing mineralization. (3) It showed estrogenic activity in MCF7 cells. These findings suggest that the beneficial effect of Onb extract on bone loss is mediated through an estrogen-like action via activation of ERalpha-ERE and ERbeta-ERE pathways and via direct action on the mineralization process of osteoblasts.

Topics: Breast Neoplasms; Calcification, Physiologic; Cell Survival; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Fabaceae; Female; Fulvestrant; Genes, Reporter; HeLa Cells; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Luciferases; Osteoblasts; Phytoestrogens; Plant Extracts; Response Elements; Transfection

Phytoestrogens are plant compounds that are structurally and functionally similar to mammalian estrogens. By competing for estrogen receptors, phytoestrogens possibly inhibit binding of the more potent endogenous estrogens and decrease their potential effects on breast cancer risk. We investigated the association between plasma phytoestrogen levels and breast cancer risk in a prospective manner.. We performed a nested case-control study within the Prospect cohort, one of the two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition. A total of 383 women (87 pre- or perimenopausal women [mean age, 52 years] and 296 postmenopausal women [mean age, 59 years]) who developed breast cancer were selected as case subjects and were matched to 383 controls, on date of blood sampling. Plasma levels of isoflavones (daidzein, genistein, glycitein, O-desmethylangolensin, and equol) and lignans (enterodiol and enterolactone) were measured. The isotope dilution liquid chromatography/tandem mass-spectrometry method incorporating triply 13C-labeled standards was used for all analyses. Breast cancer odds ratios were calculated for tertiles of phytoestrogen plasma levels using conditional logistic regression analysis.. For genistein, the risk estimate for the highest versus the lowest tertile was 0.68 (95% CI, 0.47 to 0.98). Similar protective effects, although not statistically significant, were seen for the other isoflavones. Lignan levels did not appear to be related to breast cancer risk. Results were the same in pre- or perimenopausal women, and in postmenopausal women.. High genistein circulation levels are associated with reduced breast cancer risk in the Dutch population. No effects of lignans on breast cancer risk were observed.

Topics: Age Distribution; Aged; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Cohort Studies; Confidence Intervals; Female; Follow-Up Studies; Genistein; Humans; Incidence; Middle Aged; Netherlands; Odds Ratio; Phytoestrogens; Postmenopause; Premenopause; Prospective Studies; Reference Values; Risk Assessment; Sensitivity and Specificity

Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.

Topics: Aged; Black or African American; Breast Neoplasms; Case-Control Studies; Cimicifuga; Cohort Studies; Dietary Supplements; Female; Humans; Middle Aged; Philadelphia; Phytoestrogens; Phytotherapy; Plant Extracts; Retrospective Studies; White People

In the evaluation of chemical mixture toxicity, it is desirable to develop an evaluation paradigm which incorporates some critical attributes of real world exposures, particularly low dose levels, larger numbers of chemicals, and chemicals from synthetic and natural sources. This study evaluated the impact of low level exposure to a mixture of six synthetic chemicals (SC) under conditions of co-exposure to various levels of plant-derived phytoestrogen (PE) compounds. Estrogenic activity was evaluated using an in vitro human estrogen receptor (ER) transcriptional activation assay and an in vivo immature rat uterotrophic assay. Initially, dose-response curves were characterized for each of the six SCs (methoxyclor, o,p-DDT, octylphenol, bisphenol A, beta-hexachlorocyclohexane, 2,3-bis(4-hydroxyphenyl)-propionitrile) in each of the assays. The six SCs were then combined at equipotent ratios and tested at 5-6 dose levels spanning from very low, sub-threshold levels, to a dose in which every chemical in the mixture was at its individual estrogenic response threshold. The SC mixtures also were tested in the absence or presence of 5-6 different levels of PEs, for a total of 36 (in vitro) or 25 (in vivo) treatment groups. Both in vitro and in vivo, low concentrations of the SC mixture failed to increase estrogenic responses relative to those induced by PEs alone. However, significant increases in response occurred when each chemical in the SC mixture was near or above its individual response threshold. In vitro, interactions between high-doses of SCs and PEs were greater than additive, whereas mixtures of SCs in the absence of PEs interacted in a less than additive fashion. In vivo, the SC and PE mixture responses were consistent with additivity. These data illustrate a novel approach for incorporating key attributes of real world exposures in chemical mixture toxicity assessments, and suggest that chemical mixture toxicity is likely to be of concern only when the mixture components are near or above their individual response thresholds. However, these data suggest that extrapolation from in vitro assays to in vivo mixture effects should be approached with caution.

Topics: Animals; Animals, Suckling; Breast Neoplasms; Cell Line, Tumor; Differential Threshold; Dose-Response Relationship, Drug; Drug Combinations; Drug Synergism; Endocrine Disruptors; Female; Genes, Reporter; Organ Size; Phytoestrogens; Rats; Receptors, Estrogen; Transcriptional Activation; Transfection; Uterus; Xenobiotics

Plant-derived phytoestrogens and estrogens in hormone replacement therapies have overlapping yet sometimes divergent effects on the incidence of breast cancer and osteoporosis. Using human MCF-7 breast carcinoma and G-292 osteosarcoma cell lines, it was investigated whether the phytoestrogens genistein and daidzein affect reporter gene transcription via the estrogen receptors (ERs) ERalpha and ERbeta1 as well as whether they affect the expression of estrogen-responsive genes in MCF-7 cells and the secretion of the cytokine IL-6 from G-292 cells. The results showed that genistein and daidzein potently trigger transactivation with ERbeta1 from estrogen response element-reporter genes (EC50s of 1.7-16 nM) although they were 400- to 600-fold less potent than 17beta-estradiol (E2) (EC50 of 0.02-0.04 nM). E2 was the only potent activator of ERalpha (EC50 of 0.1-0.4 nM). The rank order potency (E2 > genistein > daidzein) is maintained in MCF-7 cells as well as G-292 cells with both receptor subtypes, with a strong receptor selectivity of the phytoestrogens for ERbeta1 over ERalpha. Genistein and daidzein increased the expression of estrogen-responsive genes in MCF-7 cells. Daidzein, like E2, inhibited IL-1beta- and hormone-mediated IL-6 secretion from G-292 cells. The results provide a basis for understanding how dietary phytoestrogens protect bone without increasing the risks for breast cancer.

Topics: Breast Neoplasms; Cell Line, Tumor; Estrogen Receptor beta; Estrogens; Female; Gene Expression Profiling; Genes, BRCA1; Genistein; Humans; Interleukin-6; Isoflavones; Osteosarcoma; Phytoestrogens; Response Elements

Kola acuminate, also known as Bizzy Nut or Kola Nut, is a natural product that contains bioactive chemicals that possess hormonal properties. The purpose of this study was to characterize the putative phytoestrogenic compounds present in Bizzy Nut for estrogenic-like activity. As an initial step, five extracts (E1 - hexane, E2 - ether, E3 - acetone, E4 - methanol and E5 - water) were sequentially generated using solid-liquid phase extraction and their bioactivity was examined in MCF-7, MDA-MB-468 and LNCaP cancer cell models. MTT cell viability, dye exclusion, caspase activity and microscopic assessment of apoptotic cells demonstrated that extracts of Bizzy were cytotoxic to MCF-7, MDA-MB 468 and LNCaP cells. In MCF-7 cells, the acetone extract (E3) at 100 ppm elicited a potent cytotoxic response with a growth-inhibitory concentration (GI(50)) of 67 ppm. In contrast, E3 stimulated growth in LNCaP cells. The ether extract (E2) showed a dose-dependent cytotoxic response with a GI(50) of 13 ppm in the LNCaP cell line. Examination of the apoptotic response induced by E2 and E3 paralleled the level of cell cytotoxicity observed in both cell lines. The methanol extract (E4) was the only extract that showed a time-, dose-, and estrogen-receptor-dependent stimulation of pS2 gene expression. On the other hand, the acetone extract (E3), which showed the highest degree of cytotoxicity, showed no transcription stimulation of pS2 in MCF-7 cells. Altogether, these data indicate that Bizzy contains unique active hormonal compounds that have specific biological properties that are cell line-dependent.

Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cola; Female; Gene Expression Regulation, Neoplastic; Humans; Phytoestrogens; Plant Extracts

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.. In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).. We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.. Our results suggest that flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor-positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Endothelium, Vascular; Estradiol; Female; Flax; Humans; Lignans; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; Phytoestrogens; Umbilical Veins; Vascular Endothelial Growth Factor A

In this study, the possible molecular mechanisms involved in the estrogen-like activities of ethanol extracts from two common Chinese legumes, i.e. Adzuki bean (Phaseolus angularis Wight.) and Lima bean (Phaseolus lunatus L.) were investigated. Reverse transcription-polymerase chain reaction (RT-PCR) measurement and western blot analysis were conducted to detect the functional mRNA and protein expressions, while immunofluorescence was used to determine the estrogen receptor (ER) intracellular distribution in the MCF-7/BOS cell line. The results indicated that (1) both mRNA and protein levels of progesterone receptor (PR) in the cell line increased after 48 h treatment with the extracts compared with those in the control; (2) Adzuki and Lima bean extracts might alter the ER intracellular distributions in two different manners: for the Adzuki bean, the ER appeared in both cytoplasm and nucleus, while for the Lima bean, it exhibited the same pattern as that of estradiol in which the ER almost disappeared in the nucleus and mainly occurred in the cytoplasm. Above all, the results showed a novel pattern of ER intracellular distribution in the MCF-7/BOS cell line upon exposure to Adzuki bean extract, suggesting that different pathways were involved in the estrogen-like activities of the ethanol extracts of Adzuki bean and Lima bean.

Topics: Breast Neoplasms; Cell Line, Tumor; DNA Primers; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Neoplasms, Hormone-Dependent; Phaseolus; Phytoestrogens; Phytotherapy; Plant Extracts; Receptors, Estrogen; Receptors, Progesterone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Although 2-arylbenzofuran phytoalexins are known for decades, their anticancer activity has not been studied systematically. We have previously reported on the isolation and the estrogen receptor (ER) modulation properties of three new 2-arylbenzofurans from Onobrychis ebenoides, ebenfuran I [2-(2,4-dihydroxyphenyl)-5-hydroxy-6-methoxy-benzofuran], ebenfuran II [2-(2,4-dihydroxyphenyl)-3-formyl-4-hydroxy-6-methoxy-benzofuran] and ebenfuran III [2-(2,4-dihydroxyphenyl)-3-formyl-4-hydroxy-6-methoxy-5-(3-methyl-buten-2-yl)-benzofuran]. We now show that, while I and II could stimulate the proliferation of MCF-7 cells, III was inhibitory in a proliferation-dependent manner. III inhibited the growth of all human cancer cells examined, regardless of ER or multidrug resistance status. Estradiol rendered MCF-7 cells more sensitive to III, and this coincided with the ability of the hormone at concentrations > or = 0.1 nM to bind to the ER of the cells and stimulate their proliferation in the presence of III. Cell proliferation stimulating concentrations of I and II also enhanced the effect of III on MCF-7 cells. However, dehydroepiandrosterone and dihydrotestosterone were ineffective in this respect. III-treated MCF-7 cells exhibited G1 phase arrest followed by detachment-induced cell death and/or apoptosis in the adherent fraction, pronounced induction of Bax and suppression of estradiol induction of Bcl-2. Our data indicate that the largely unexplored pool of benzofuran phytoalexins includes entities potentially suitable for chemoprevention and treatment of human cancer.

Topics: Adrenal Glands; Antineoplastic Agents, Phytogenic; Benzofurans; Breast Neoplasms; Catechols; Cell Proliferation; Cell Survival; Cytotoxins; Drug Interactions; Furans; Gonadal Steroid Hormones; HeLa Cells; HT29 Cells; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Phytoalexins; Phytoestrogens; Sesquiterpenes; Steroids; Terpenes; Tumor Cells, Cultured

In the public opinion, phytochemicals (PCs) present in the human diet are often considered beneficial (e.g. by preventing breast cancer). Two possible mechanisms that could modulate tumor growth are via interaction with the estrogen receptor (ER) and inhibition of aromatase (CYP19). Multiple in vitro studies confirmed that these compounds act estrogenic, thus potentially induce tumor growth, as well as aromatase inhibitory, thus potentially reduce tumor growth. It is thought that in the in vivo situation breast epithelial (tumor) cells communicate with surrounding connective tissue by means of cytokines, prostaglandins and estradiol forming a complex feedback mechanism. Recently our laboratory developed an in vitro co-culture model of healthy mammary fibroblasts and MCF-7 cells that (at least partly) simulated this feedback mechanism (M. Heneweer et al., TAAP vol. 202(1): 50-58, 2005). In the present study biochanin A, chrysin, naringenin, apigenin, genistein and quercetin were studied for their estrogenic properties (cell proliferation, pS2 mRNA) and aromatase inhibition in MCF-7 breast tumor cells, healthy mammary fibroblasts and their co-culture. The proliferative potency of these compounds in the MCF-7 cells derived from their EC(50)s decreased in the following order: estadiol (4*10(-3) nM)>biochanin A (9 nM)>genistein (32 nM)>testosterone (46 nM)>naringenin (287 nM)>apigenin (440 nM)>chrysin (4 microM). The potency to inhibit aromatase derived from their IC(50)s decreased in the following order: chrysin (1.5 microM)>naringenin (2.2 microM)>genistein (3.6 microM)>apigenin (4.1 microM)>biochanin A (25 microM)>quercetin (30 microM). The results of these studies show that these PCs can induce cell proliferation or inhibit aromatase in the same concentration range (1-10 microM). Results from co-cultures did not elucidate the dominant effect of these compounds. MCF-7 cell proliferation occurs at concentrations that are not uncommon in blood of individuals using food supplements. Results also indicate that estrogenicity of these PCs is quantitatively more sensitive than aromatase inhibition. It is suggested that perhaps a more cautionary approach should be taken for these PCs before taken as food supplements.

Topics: Adenocarcinoma; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Communication; Cell Line, Tumor; Cell Proliferation; Coculture Techniques; Dietary Supplements; Estrogen Receptor Modulators; Fibroblasts; Humans; Mammary Glands, Human; Phytoestrogens

To explore the phytoestrogenic effects of ten kinds of Chinese medicine including flos carthami, radix cyathulae, radix salviae miltiorrhizae, fructus ligustri lucidi, fructus lycii, radix clycyrrhizae, herba cistanches, herba epimedii, fructus psoraleae and semen cuscutae.. 240 female Kunming mice weighting 9 - 12 g were randomly divided into two main groups A and B. A group was divided into 12 small groups: 1 solvent control group, 1 diethylstilbestrol control group and 10 Chinese medicine groups. B group was also divided into 12 small groups: 1 solvent control group, 1 diethylstilbestrol control group and 10 Chinese medicine antagonistic groups. Mice in ten antagonistic groups were administered both Chinese medicine and diethylstilbestrol everyday. After administered(op) for 4 days, blood was collected and serum was separated. The effect of the pharmacological serum on proliferation rate of MCF-7 (ER+) was analyzed by MTT-assay.. In A group, proliferation rates of MCF-7 cells treated with serum from eight Chinese medicine groups including flos carthami, radix cyathulae, radix salviae miltiorrhizae, fructus lycii, herba cistanches, herba epimedii, fructus psoraleae and semen cuscutae were coued markedly increase respectively. While serum from fructus ligustri lucidi group could markedly decrease the proliferation rate of MCF-7 cells. In B group, the increased proliferation rate of MCF-7 cells caused by diethylstilbestrol was significantly reduced in seven Chinese medicine antagonistic groups including flos carthami, radix cyathulae, radix salviae miltiorrhizae, radix clycyrrhizae, herba epimedii, fructus psoraleae and semen cuscutae. While the increased proliferation rate could be markedly enhanced in herba cistanches group.. Six kinds of Chinese medicine such as flos carthami, radix cyathulae, radix salviae miltiorrhizae, herba epimedii, fructus psoraleae and semen cuscutae show both estrogenic effects (when administered indepently) and antiestrogenic effects (when administered together with diethylstilbestrol). Such bidirectional effects depends on the internal estrogen level.

Topics: Animals; Breast Neoplasms; Carthamus tinctorius; Cell Line, Tumor; Cell Proliferation; Cell Survival; Diethylstilbestrol; Drug Antagonism; Drugs, Chinese Herbal; Estrogens, Non-Steroidal; Female; Humans; Mice; Phytoestrogens; Plants, Medicinal; Random Allocation; Receptors, Estrogen; Salvia miltiorrhiza; Serum

Lignans are plant polyphenols which may possess anticancer, antioxidant, antimicrobial, anti-inflammatory and immunomodulatory activities. In particular, the lignan 7-hydroxymatairesinol (HMR/lignan, HMR) is a novel precursor of the mammalian lignan enterolactone (EL). In the present study, we investigated the estrogenicity of HMR and of EL in comparison to estradiol (E2), by measuring their effects on growth and apoptotic markers in the human estrogen-sensitive cell line MCF-7. HMR, EL and E2 concentration-dependently increased the percentage of MCF-7 cells in the S phase of the cell cycle, with the following relative potencies: E2 congruent with EL>>HMR, and efficacies: E2>HMR>>EL. Treatment of MCF-7 cells with either HMR, EL or E2 also increased the Bcl-2/Bax mRNA ratio. The effects of HMR and EL were reduced in the presence of the estrogen receptor (ER) antagonist tamoxifene. We conclude that both HMR and its metabolite EL are endowed with estrogenic activity, which is likely to be exerted through the contribution of ER-dependent pathways and to target the same intracellular mechanisms acted upon by E2. The estrogenicity of HMR and EL is however milder than that of E2, as indicated by the lower potencies and efficacies of both lignans. The present results support the notion that dietary supplementation with HMR may result in a mild estrogenic activity, both directly and by providing a suitable source for endogenous EL.

Topics: 4-Butyrolactone; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Female; Gene Expression Regulation, Neoplastic; Humans; Lignans; Phytoestrogens; Picea; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Tamoxifen

Our previous studies have shown that genistein can enhance the insulin-like growth factor (IGF)-1 receptor signalling pathway via an oestrogen receptor (ER) in human breast cancer MCF-7 cells. The present study aims to investigate how genistein regulates IGF-1 receptor expression in human MCF-7 cells. Genistein at 1 microm stimulated the growth of MCF-7 cells and this effect could be completely blocked by the IGF-1 receptor antagonist JB-1, suggesting that IGF-1 receptor is essential for mediating the proliferative effects of genistein in MCF-7 cells. Genistein increased IGF-1 receptor promoter activity. This effect could be completely abolished by co-treatment of MCF-7 cells with ICI 182,780 (10- 6 m). Genistein increased IGF-1 receptor gene expression and this effect could be completely blocked by the IGF-1 receptor antagonist JB-1. Co-treatment of MCF-7 cells with cycloheximide (5 microg/ml) completely blocked the induction of IGF-1 receptor protein and mRNA expression by genistein. The results indicated that the induction of IGF-1 receptor promoter activity by genistein required the action of ER while the stimulatory actions of genistein on IGF-1 receptor expression required the activity of the IGF-1 receptor and de novo protein synthesis. These data provide evidence to support the hypothesis that the inductive effects of genistein on IGF-1 receptor expression require the cross-talk between IGF-1 receptor and the ER-dependent pathways.

Topics: Analysis of Variance; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogen Receptor Modulators; Female; Fulvestrant; Gene Expression; Gene Expression Regulation, Neoplastic; Genistein; Humans; Phytoestrogens; Receptor, IGF Type 1; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; Transfection

The study reported here was designed to determine whether a phytoestrogen-containing soy extract (SSE) could negate/overwhelm the inhibitory effects of ICI 182 780 on the growth of estrogen-sustained human breast cancer xenografts (MCF-7), in ovariectomized athymic mice. As expected, estradiol-supplemented tumors did not grow over the study period in ICI 182 780-treated females; concomitant administration of 50 mg/kg per day SSE slightly potentiated the inhibitory activity of the drug, while at 100 mg/kg per day, SSE partially negated ICI 182 780 activity. In keeping with these in vivo outcomes, we observed that the level of cyclin D1 (and progesterone receptor) in MCF-7 xenografts was considerably reduced by ICI 182 780, an effect enhanced by concomitant treatment with 50 SSE, but reduced by the higher dosage (i.e. 100 mg/kg per day). Thrombospondin-1 (TSP-1) and kallikrein 6 (KLK6) levels were also reduced following ICI 182 780, although to a lesser degree; again, combined anti-estrogen and SSE produced a dose-dependent regulation in TSP-1 and KLK6 tumor level, with a further reduction in the mRNA gene expression at 50 SSE (compared with ICI 182 780) and a partial reversion of the drug-induced down-regulation at 100 mg/kg per day. No modulation was detected in the serum concentration of IGF-1 (a potent mitogen for estrogen receptor-positive breast cancer cell lines) either upon treatment with ICI 182 780 or concomitant administration of the anti-estrogen with SSE. In conclusion, results from this study raise concerns about the consumption of isoflavone supplements in conjunction with ICI 182 780 therapy, in postmenopausal women with estrogen-dependent breast cancer.

Topics: Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Proliferation; Disease Models, Animal; Drug Synergism; Estradiol; Estrogens; Female; Fulvestrant; Glycine max; Humans; Kallikreins; Mice; Mice, Nude; Neoplasms, Hormone-Dependent; Organ Size; Phytoestrogens; Plant Extracts; RNA, Messenger; Thrombospondin 1; Uterus; Xenograft Model Antitumor Assays

Genistein and daidzein are the main isoflavones in legumes. Equol is an intestinal bacterial metabolite of daidzein. In this study, we evaluated the estrogenic potential of daidzein and synthetic (+/-)-equol to stimulate growth of estrogen-dependent breast cancer (MCF-7) in vitro and in vivo. We hypothesize that estrogenic effects of daidzein and (+/-)-equol could modulate the growth of MCF-7 cells both in vitro and also once implanted into ovariectomized athymic mice. At concentrations between 0.001 and 50 microM, daidzein and (+/-)-equol stimulated the growth of MCF-7 cells with maximal stimulation at 1 muM in vitro. To evaluate their effects on the growth of MCF-7 cells implanted in ovariectomized athymic mice, two dietary dose-response studies [daidzein (125, 250, 500 and 1000 p.p.m.) and (+/-)-equol (250, 500 and 1000 p.p.m.)] were conducted. Tumor size and body weight were monitored weekly during the study. At completion of the study, we analyzed cellular proliferation of tumors using immunohistochemical staining (ki-67), pS2 expression in tumors using a real time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and total daidzein and (+/-)-equol levels in plasma using liquid chromatography-electrospray tandem mass spectrometry (LC-ES/MS/MS). Dietary daidzein had a slight but significant stimulatory effect on MCF-7 tumor growth in mice. No significant induction of pS2 mRNA (an estrogen-responsive marker) in tumors by dietary daidzein was observed. Total plasma daidzein concentrations in plasma were between 0.25 and 1.52 microM. Dietary equol treatment (for 37 weeks) did not stimulate MCF-7 tumor growth. There were no statistical differences in tumor size, proliferation and pS2 expression among any treatment groups. Total equol concentrations in plasma were 2.10-3.21 microM. In conclusion, daidzein and (+/-)-equol have proliferative effects on MCF-7 cell growth in vitro within the concentration range tested. Dietary daidzein had a slight but significant stimulatory effect on tumor growth, whereas (+/-)-equol did not stimulate the growth of estrogen-dependent breast tumor growth in athymic mice, increase the cell proliferation in tumors, or induce an estrogen-responsive pS2 expression. Total daidzein or (+/-)-equol plasma levels in mice fed the isoflavones were in the range that stimulated MCF-7 cell growth in vitro. These results suggest that pharmacokinetic and/or metabolic factors attenuate the estrogenic effects of daidzein

Topics: Animals; Breast Neoplasms; Cell Proliferation; Disease Progression; Dose-Response Relationship, Drug; Equol; Female; Humans; Isoflavones; Mice; Mice, Nude; Ovariectomy; Phytoestrogens; Transplantation, Heterologous

Breast cancer is the most common cancer in women and a significant cause of death. Mutations of the oncosuppressor genes BRCA1 and BRCA2 are associated with a hereditary risk of breast cancer, and dysregulation of their expression has been observed in sporadic cases. Soya isoflavones have been shown to inhibit breast cancer in studies in vitro, but associations between the consumption of isoflavone-containing foods and breast cancer risk have varied in epidemiological studies. Soya is a unique source of the phytoestrogens daidzein (4',7-dihydroxyisoflavone) and genistein (4',5,7-trihydroxyisoflavone), two molecules that are able to inhibit the proliferation of human breast cancer cells in vitro. The aim of the present study was to determine the effects of genistein (5 microg/ml) and daidzein (20 microg/ml) on transcription in three human breast cell lines (one dystrophic, MCF10a, and two malignant, MCF-7 and MDA-MB-231) after 72 h treatment. The different genes involved in the BRCA1 and BRCA2 pathways (GADD45A, BARD1, JUN, BAX, RB1, ERalpha, ERbeta, BAP1, TNFalpha, p53, p21Waf1/Cip1, p300, RAD51, pS2, Ki-67) were quantified by real-time quantitative RT-PCR, using the TaqMan method and an ABI Prism 7700 Sequence Detector (Applied Biosystems). We observed that, in response to treatment, many of these genes were overexpressed in the breast cancer cell lines (MCF-7 and MDA-MB-231) but not in the dystrophic cell line (MCF10a).

Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Genes, BRCA1; Genes, BRCA2; Genes, Tumor Suppressor; Genistein; Glycine max; Humans; Isoflavones; Phytoestrogens; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transcription, Genetic

Red clover (Trifolium pratense L., Fabaceae) dietary supplements are currently used to treat menopausal symptoms because of their high content of the mildly estrogenic isoflavones daidzein, genistein, formononetin, and biochanin A. These compounds are estrogenic in vitro and in vivo, but little information exists on the best time to harvest red clover fields to maximize content of the isoflavones and thus make an optimal product. Samples of cultivated red clover above-ground parts and flower heads were collected in parallel over one growing season in northeastern Illinois. Generally, autohydrolytic extracts of above-ground parts contained more isoflavones and had more estrogenic activity in Ishikawa endometrial cells as compared with extracts of flower heads. Daidzein and genistein contents peaked around June to July, while formononetin and biochanin A contents peaked in early September. Flower head and total above-ground parts extracts exhibited differential estrogenic activity in an Ishikawa (endometrial) cell-based alkaline phosphatase induction assay, whereas nondifferential activity was observed for most extracts tested in an MCF-7 (breast) cell proliferation assay when tested at the same final concentrations. Ishikawa assay results could be mapped onto the extracts' content of individual isoflavones, but MCF-7 results did not show such a pattern. These results suggest that significant metabolism of isoflavones may occur in MCF-7 cells but not in Ishikawa cells; therefore, caution is advised in the choice of bioassay used for the biological standardization of botanical dietary supplements.

Topics: Breast Neoplasms; Cell Division; Cell Line; Cell Line, Tumor; Endometrium; Female; Humans; Isoflavones; Phytoestrogens; Seasons; Trifolium

Women approaching menopause increasingly investigate alternatives to hormone replacement therapy. Plant phytoestrogens are being promoted as "natural" alternatives but there is a lack of substantive data to advocate their safe use in breast cancer patients receiving tamoxifen (TAM), or in those who have relapsed. The aim of our study was to investigate the proliferative effects and mode of action of the phytoestrogens genistein, daidzein and coumestrol on TAM-sensitive (-s) and resistant (-r) breast cancer cells under in vitro conditions designed to mimic the hormonal environment of the pre- and post-menopausal breast. At physiological concentrations (<10 microM) and under reduced estrogen (E2) conditions, genistein was mitogenic to TAM-s cells with TAM-r cells generally refractory. Daidzein and coumestrol were growth stimulatory irrespective of TAM sensitivity. Transcriptional activity was ERE-mediated. Combining phytoestrogens with E2 (simulating the pre-menopausal breast environment) had no effect on growth of TAM-s or TAM-r cells. Addition of 4-HT mimicked the hormonal environment in post-menopausal breast cancer patients receiving TAM. The growth inhibitory effects of 4-HT were abrogated in TAM-s cells when combined with genistein and coumestrol, and to a lesser extent, daidzein, where significant growth stimulatory effects were observed. In TAM-r cells, proliferation did not exceed control values. At phytoestrogen concentrations above 10 microM, growth inhibitory effects were seen, irrespective of estrogenic environment or cell sensitivity to TAM. Our in vitro data suggests that phytoestrogens could have potentially adverse mitogenic effects on tumour cells and should probably be avoided by patients who remain sensitive to TAM or in those with pre-existing and possibly undiagnosed breast tumours.

Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Coumestrol; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Gene Expression; Genistein; Humans; Isoflavones; Luciferases; Phytoestrogens; Receptors, Progesterone; Response Elements; Tamoxifen; Transfection

We examined the association of dietary lignan intake with estrogen receptor negative (ER-) and ER positive (ER+) breast cancer risk in a breast cancer case-control study. Among premenopausal women only, there was a reduced risk of ER- breast cancer for those in the highest compared to the lowest quartile of lignan intake suggesting that the observed negative association of lignans with breast cancer may be limited to ER- tumors.

Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Diet; Female; Humans; Lignans; Middle Aged; New York; Odds Ratio; Phytoestrogens; Postmenopause; Premenopause; Receptors, Estrogen; Risk Assessment; Risk Factors

High consumption of phytoestrogen-rich food correlates with reduced incidence of breast cancer. However, the effect of phytoestrogens on growth of pre-existing breast tumors presents concerns when planning the use of phytoestrogens as chemoprevention st rategy. Genistein, the active phytoestrogen in soy, displays weak estrogenic activity mediated by estrogen receptor (ER) with a preferential binding for the ER-beta species. However, no information is at present available on the interaction between phytoestrogens and the various isoforms generated by alternative splicing. In two human breast cancer cell lines, T47D and BT20, which express variable levels of ER-beta, the effect of genistein and quercetin was evaluated singly and in comparison with 17beta-estradiol, on mRNA expression of estrogen receptor-beta (ER-beta) isoforms evaluated by a triple primer RT-PCR assay. In T47D cells estradiol caused a 6-fold up-regulation of total ER-beta, and modified the relative expression pattern of the various isoforms, up-regulating the beta2 and down-regulating the beta5 isoform. Genistein up-regulated ER-beta2 and ER-beta1 in T47D cells, and after treatment the ER-beta2 isoform became prevalent, while in BT20 cells it almost doubled the percent contribution of ER-beta1 and ER-beta2 to total ER-beta. Quercetin did not alter the total levels nor the percent distribution of ER-beta isoforms in either cell line. Genistein, through the modulation of ER-beta isoform RNA expression inhibited estrogen-promoted cell growth, without interfering on estrogen-regulated transcription. ER-beta and its ER-beta mRNA isoforms may be involved in a self-limiting mechanism of estrogenic stimulation promoted either by the natural hormone or by weaker estrogen agonists like genistein.

Topics: Breast Neoplasms; Cell Line, Tumor; DNA Primers; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Genistein; Humans; Phytoestrogens; Quercetin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The scientific debate on the role of dietary phytoestrogens for prevention of breast cancer is still ongoing. We previously reported an inverse association between dietary phytoestrogen intake and premenopausal breast cancer risk and now examine the relationship with plasma phytoestrogen concentrations.. We measured enterolactone (mammalian lignan) and genistein (isoflavone) concentrations in plasma samples of 220 premenopausal cases and 237 age-matched controls from a population-based case-control study in Germany.. Median plasma enterolactone concentrations in cases and controls were 6.3 and 9.7 nmol/l, respectively, and median genistein concentrations were 4.5 and 3.7 nmol/l, respectively. Premenopausal breast cancer risk decreased with increasing plasma enterolactone concentrations. Adjusted odds ratios (95% confidence intervals) were 0.42 (0.20-0.90) and 0.38 (0.17-0.85) (P for trend 0.007) for women in the third and fourth quartile of plasma enterolactone compared to those in the lowest quartile. There was no significant association between plasma genistein concentration and premenopausal breast cancer risk.. Using biomarkers of phytoestrogen intake, we confirmed the strong inverse association between enterolactone and premenopausal breast cancer risk as found with dietary intake estimates. This result gives support to the potential role of mammalian lignans for breast cancer prevention among premenopausal women in Western populations.

Topics: 4-Butyrolactone; Adult; Breast Neoplasms; Case-Control Studies; Diet; Female; Genistein; Humans; Lignans; Middle Aged; Phytoestrogens; Plant Preparations; Premenopause; Risk Factors

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on E2 concentration (< or = 10(-12) M). Kaempferol (10(-5) M) also caused antiproliferative effect on MCF-7 cell in the presence of E2 (10(-11) M) and restored to the addition of excess E2 (10(-7) M), which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at 10(-4) M, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected (10(-5) M), kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess E2 (10(-7) M) indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by E2, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Female; Gene Expression Regulation; Humans; Kaempferols; Luciferases; Phytoestrogens; Receptors, Estrogen; Response Elements; RNA, Messenger; Transfection; Trefoil Factor-1; Tumor Stem Cell Assay; Tumor Suppressor Proteins; Vitellogenins

Fractionation of the neutral extract of Onobrychis ebenoides (Leguminosae) yielded a new isoflavone, named ebenosin (1), in addition to the known ones, afrormosin (2), formononetin (3) and daidzein (4). Although the relative binding affinities of 1 - 4 for estrogen receptor alpha (ERalpha) were nearly comparable and matched those of 1-3 for ERbeta, that of 4 for the latter receptor was significantly higher than any of the other. Compounds 1 - 4 induced cell proliferation and gene expression in breast and endometrial cancer cells in an ER-dependent manner. Nonetheless, the rank order of induction potencies ( 4 > 3 >or= 2 >or= 1) matched better that of affinities for ERbeta ( 4 > 3 >or= 2 >or= 1) rather than ERalpha ( 4 >or= 3 >or= 2 >or= 1). While the antiestrogen ICI 182,780 could inhibit the induction of proliferation of ER-positive breast cancer cells by 1-4, it could not prevent 1 from exhibiting significant ER-independent cytotoxicity at 10 microM. By contrast, 1 was much less cytotoxic and only weakly estrogenic for ER-positive endometrial adenocarcinoma cells. In conclusion, our data suggest that the C-8 isoprenyl substituent of 1 renders it cytotoxic and/or estrogenic in a cell-dependent manner.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Fabaceae; Female; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Phytoestrogens; Phytotherapy; Plant Extracts; Structure-Activity Relationship

Epidemiological studies indicate that Asian women have a lower incidence of breast cancer compared with their counterparts in the West, and soya consumption has been suggested as a contributory factor. Clinical and animal studies have revealed that cyclooxygenase-2 (COX-2) expression is associated with a risk of breast cancer. In the present study, we investigated the effect of soya isoflavones on the expression of COX-2 in the breast cell line MCF-7. Genistein, daidzein and equol were found to inhibit COX-2 expression induced by phorbol 12-myristate 13-acetate (PMA). Similar findings were observed in the COX-2 protein analysis. In order to study transcriptional control, a fragment of the 5'-flanking region of the hCOX-2 gene was amplified and inserted into a firefly luciferase reporter plasmid. The reporter assay indicated that the transactivation of the hCOX-2 promoter was induced by PMA, and activity was inhibited with the co-administration of genistein, daidzein or equol. An activator protein-1 (AP-1)/cyclic AMP response element binding protein (CREB) binding site (-59/-53) was identified in hCOX-2 promoter, and this could be critical in PMA-induced COX-2 expression. Truncation reporter plasmids with (-70/-36) and without (-51/-36) AP-1/CREB were constructed for subsequent analysis. The results revealed that the hCOX-2 promoter transactivation suppressed by isoflavone could be dependent on AP-1/CREB binding. Nonetheless, this study illustrated that the soya isoflavones reduced COX-2 expression, which could be important in the post-initiation events of breast carcinogenesis.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Equol; Female; Genistein; Glycine max; Humans; Isoflavones; Membrane Proteins; Phytoestrogens; Plant Extracts; Promoter Regions, Genetic; Tetradecanoylphorbol Acetate

It has been postulated that the R- and S-equol enantiomers have different biological properties given their different binding affinities for the estrogen receptor. S-(-)equol is produced via the bacterial conversion of the soy isoflavone daidzein in the gut. We have compared the biological effects of purified S-equol to that of racemic (R and S) equol on breast and prostate cancer cells of varying receptor status in vitro. Both racemic and S-equol inhibited the growth of the breast cancer cell line MDA-MB-231 (> or = 10 microM) and the prostate cancer cell lines LNCaP (> or = 5 microM) and LAPC-4 (> or = 2.5 microM). The compounds also showed equipotent effects in inhibiting the invasion of MDA-MB-231 and PC-3 cancer cells through matrigel. S-equol (1, 10, 30 microM) was unable to prevent DNA damage in MCF-7 or MCF-10A breast cells following exposure to 2-hydroxy-4-nonenal, menadione, or benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide. In contrast, racemic equol (10, 30 microM) prevented DNA damage in MCF-10A cells following exposure to 2-hydroxy-4-nonenal or menadione. These findings suggest that racemic equol has strong antigenotoxic activity in contrast to the purified S-equol enantiomer implicating the R-, rather than the S-enantiomer as being responsible for the antioxidant effects of equol, a finding that may have implications for the in vivo chemoprotective properties of equol.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Division; Cell Line, Tumor; Comet Assay; DNA Damage; DNA, Neoplasm; Dose-Response Relationship, Drug; Equol; Female; Humans; Isoflavones; Male; Phytoestrogens; Prostatic Neoplasms; Receptors, Estrogen; Stereoisomerism

To explore the estrogenic activity of ethanol extract from adzuki bean Phaseolus angularis and its effect on progesterone receptor (PR) level of human breast cancer MCF-7 cells.. The modified MCF-7 cell proliferation assay was used to evaluate the estrogenic activity of adzuki bean extract. And its effect on PR mRNA and protein were addressed using RT-PCR measurements and western blotting analysis respectively in which pure estrogen receptor antagonist ICI 182,780 was employed as the tool.. The estrogenic activity of adzuki bean extract at various concentrations (10-200 microg x mL(-1)), expressed as proliferative effect (PE) relative to that of solvent control, was examined. The results indicated that the extract of adzuki bean was able to induce MCF-7 cell growth with a maximum at 100 microg x mL(-1). The results of RT-PCR and western blotting showed that PR mRNA and protein could be significantly induced by adzuki bean extract in MCF-7 cells. Moreover, the specific estrogen receptor antagonist ICI 182,780 could block these reactions.. Ethanol extract of adzuki bean has the estrogen-like activities through the estrogen response pathway.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drugs, Chinese Herbal; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Humans; Phaseolus; Phytoestrogens; Plants, Medicinal; Receptors, Progesterone; RNA, Messenger; Seeds

It has been suggested that dietary phytoestrogen intake during adolescence may reduce the risk of developing breast cancer. This population-based case-control study evaluated the association between adolescent dietary phytoestrogen intake and adult breast cancer risk among women in Ontario, Canada.. Pathology-confirmed, population-based breast cancer cases, aged 25-74 years, diagnosed between June 2002 and April 2003, were identified using the Ontario Cancer Registry. Population-based controls were recruited, and matched to cases within 5-year age groups. Adolescent phytoestrogen intake was obtained using a brief food frequency questionnaire (n = 3,024 cases, n = 3,420 controls). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).. Higher phytoestrogen intake (both isoflavones and lignans) during adolescence was associated with a reduced breast cancer risk, and a monotonic trend was observed from the lowest to the highest quartile (OR [Q2] = 0.91, 95% CI 0.79-1.04, OR[Q3] = 0.86, 95% CI 0.75-0.98, and OR[Q4] = 0.71, 95% CI 0.62-0.82, p-trend < 0.001).. Adolescent dietary phytoestrogen intake may be associated with a decreased risk of adult breast cancer. If verified, this finding has important implications with regard to breast cancer prevention since diet is a potentially modifiable factor.

Topics: Adolescent; Breast Neoplasms; Canada; Case-Control Studies; Diet; Disease Susceptibility; Female; Humans; Odds Ratio; Phytoestrogens; Registries; Risk Factors

Topics: Abnormalities, Drug-Induced; Adult; Animals; Breast Neoplasms; DDT; Endocrine Disruptors; Environmental Exposure; Environmental Pollutants; Estradiol Congeners; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Infant, Newborn; Infertility, Male; Male; Pesticides; Phytoestrogens; Pregnancy; Spain; Toxicology; Universities

Topics: Breast Neoplasms; Case-Control Studies; Diet; Female; France; Humans; Middle Aged; Phytoestrogens; Premenopause; Prospective Studies

Breast cancer incidence is lower and survival is longer in Asian women residing in Japan, China, or the Philippines than Caucasian women residing in the United States. Phytoestrogen intake has been examined as a possible reason for the disparity in breast cancer incidence and survival. This study examined the association between phytoestrogen intake prior to diagnosis of breast cancer and indicators of breast cancer prognosis (tumor size, estrogen and progesterone receptor status, histological grade, lymphovascular invasion, nodal spread, and stage) in 128 women, aged 40-79 yr, newly diagnosed with invasive breast cancer. After controlling for significant confounding factors, higher intakes of phytoestrogens were associated with favorable indicators of breast cancer. In women with higher intakes of phytoestrogens, there was a 32% reduction in the odds of being diagnosed with any stage of cancer other than stage 1 (95% confidence interval, CI = 0.49-0.93; P = 0.02), a 38% reduction in odds of being diagnosed with positive lymphovascular invasion (95% CI = 0.40-0.95; P = 0.03), and a 66% increase in the odds of being diagnosed with a positive progesterone receptor (95% CI = 1.06-2.58; P = 0.03). We conclude that phytoestrogen intake prior to diagnosis may improve prognosis of breast cancer.

Topics: Adult; Aged; Anticarcinogenic Agents; Breast Neoplasms; Confidence Intervals; Diet; Female; Humans; Incidence; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Odds Ratio; Phytoestrogens; Postmenopause; Premenopause; Prognosis; Receptors, Progesterone; Risk Factors; Survival Analysis

Quinone reductase (QR) is a phase II detoxification enzyme that plays an important role in detoxifying quinones and may help maintain the antioxidant function of the cell. We have previously observed that QR is up-regulated by anti-oestrogens, but not oestrogen, in breast cancer cells via ERbeta (oestrogen receptor beta) transactivation. Such QR induction appears to protect breast cells against oestrogen-induced oxidative DNA damage, most likely by reducing reactive oestrogen metabolites termed catecholestrogen-quinones back to the hydroxy-catecholestrogens which may be conjugated. We now report that the phytoestrogens biochanin A, genistein and resveratrol also up-regulate QR expression in breast cancer cells. We observe that regulation can occur at the transcriptional level, preferentially through ERbeta transactivation at the electrophile response element of the QR gene promoter. By chromatin immunoprecipitation analysis, we show binding of ERalpha and ERbeta to the QR promoter, with increased ERbeta binding in the presence of resveratrol. Functional studies show that biochanin A and resveratrol, but not genistein, can significantly protect against oestrogen-induced oxidative DNA damage in breast cancer cells. Antisense technology was used to determine whether such protection was dependent on ERbeta or QR. Our results with resveratrol are consistent with our hypothesis that the protective ability of resveratrol is partially dependent on the presence of ERbeta and QR. In conclusion, we postulate that phytoestrogen-mediated induction of QR may represent an additional mechanism for breast cancer protection, although the effects may be specific for a given phytoestrogen.

Topics: Breast Neoplasms; Cell Line, Tumor; DNA Damage; Enzyme Induction; Estrogen Receptor beta; Estrogens; Genistein; Humans; Ligands; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Phytoestrogens; Response Elements; Resveratrol; Stilbenes; Transcription, Genetic

The estrogenic activity of several intermediary plant compounds has raised concern about possible risks of unwanted interference with endocrine regulation, but on the other hand there are potential medical benefits, in particular in treatment of menopausal symptoms or cancer. In the present study, we compare the estrogenic effects of phytoestrogens naringenin, 8-prenylnaringenin, 6-(1,1-dimethylallyl)naringenin, and the synthetic 4'-acetyl-7-prenyloxynaringenin. Two mammalian in vitro systems and a fish in vivo system were used to study the estrogenic properties with reference to genistein, 17-beta-estradiol or ethynylestradiol. Strong differences were observed between the mammalian in vitro and the fish in vivo test system. In the medaka sex reversal/vtg gene expression assay no estrogenic effects of the naringenin-type flavonoids were observed, while mammalian in vitro systems showed a similar and graded response to the test compounds.

Topics: Animals; Breast Neoplasms; Cell Line; Dose-Response Relationship, Drug; Estrogens; Flavanones; Flavonoids; Genistein; Humans; Oryzias; Phytoestrogens; Receptors, Estrogen; Sex Differentiation; Species Specificity

Cross-sectional studies investigating the relationship between phytoestrogens in diet, urine, or blood with plasma estradiol and sex hormone binding globulin (SHBG) have been inconclusive. We investigated the relationship among phytoestrogen exposure, polymorphisms in the ESR1, COMT, CYP19, and SHBG genes, and plasma estradiol and SHBG levels in 125 free-living postmenopausal women taking part in a cohort study (European Prospective Investigation of Cancer and Nutrition-Norfolk) using three different markers: dietary, urinary, and serum phytoestrogens. Phytoestrogen levels (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) in spot urine and serum were analyzed by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, respectively. Plasma estradiol and SHBG were measured by immunoassays. Adjusting for age and body mass index, urinary daidzein, genistein, glycitein, and serum daidzein and glycitein were negatively correlated with plasma estradiol (R = -0.199 to -0.277, P <0.03), with particularly strong associations found in the 18 women with CC genotype for ESR1 PvuII polymorphism (R = -0.597 to -0.834, P < 0.03). The negative correlations observed between isoflavones and estradiol in women as a whole became no longer significant when we excluded women with ESR1 PvuII CC genotype, indicating that the correlations observed were due mainly to this group of women. There was no relationship between dietary isoflavones and plasma estradiol and no association was found between any of the dietary, urinary, and serum phytoestrogen and plasma SHBG or between these factors and polymorphisms in CYP19, SHBG, and COMT. We conclude that higher isoflavone exposure is associated with lower plasma estradiol in postmenopausal women and that this preliminary study is suggestive of the involvement of diet-gene interactions.

Topics: Aged; Analysis of Variance; Biomarkers, Tumor; Breast Neoplasms; Chromatography, Gas; Cross-Sectional Studies; Diet; Estradiol; Europe; Female; Genotype; Humans; Mass Spectrometry; Middle Aged; Phytoestrogens; Polymorphism, Genetic; Postmenopause; Prospective Studies; Sex Hormone-Binding Globulin; Statistics, Nonparametric

Wild-type erbB-2/neu transgenic mice were used to study the interactions between tamoxifen and dietary phytoestrogens (or isoflavones) by dose and form in vivo. Mice were randomized to one of four dietary formulas and implanted with an 8-week continuous-release tamoxifen or placebo pellet at 8 weeks of age. In placebo-treated mice, soy meal diet (but not diets supplemented with low-dose or high-dose isoflavones or a casein diet) resulted in prolongation of tumor latency. In tamoxifen-treated mice fed the soy meal, casein, or high-dose isoflavone enriched diets, the majority (>80%) showed no tumor formation by 60 weeks of age. Of the mice that developed tumors, latency was significantly prolonged. In tamoxifen-treated mice fed the low-dose isoflavone enriched diet, a much higher rate of mammary tumor development (>50%; P < 0.002) and a shorter tumor latency were observed. In vitro studies of human and mouse mammary tumor cell lines confirm that low doses of genistein, co-administered with tamoxifen, promote cell proliferation. This is in contrast to tamoxifen alone or tamoxifen with higher doses of genistein that are growth inhibitory. In summary, low-dose dietary isoflavones abrogated tamoxifen-associated mammary tumor prevention in vivo. These interactions are supported by in vitro data from human and mouse mammary tumor cell lines. These dose-associated interactions likely have relevance to the human use of tamoxifen for prevention or treatment of breast cancer.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Isoflavones; Mammary Neoplasms, Experimental; Mice; Mice, Transgenic; Phytoestrogens; Tamoxifen

Topics: Alzheimer Disease; Breast Neoplasms; Cardiovascular Diseases; Colorectal Neoplasms; Dehydration; Estrogen Replacement Therapy; Estrogens; Female; Hot Flashes; Humans; Menopause; Osteoporosis; Phytoestrogens; Progesterone; Urination Disorders; Vaginal Diseases

To investigate the estrogen-like activities of icariin (ICA), icaritin (ICT) and desmethylicaritin (DICT) and their structure/activity relationships.. ICT was hydrolyzed from ICA by cellulase and then DICT was demethylated from ICT in boron tribromide and dichloromethane system. Estrogen-sensitive MCF-7 cells and T47D cells were co-incubated with different concentrations of test compounds for 6 and 9 d respectively, and the cell proliferation was measured by MTT.. ICT and DICT both markedly enhanced cell proliferation. Compared with estradiol (10.(-9) mol/L), the proliferative effects of 10.-6 mol/L ICT and DICT on MCF-7 cells were 90.0% and 94.0% (P<0.01), respectively, and those of T47D cells were 65.6% and 50.0%. (P<0.01). But this phenomenon was not observed with ICA. Cell proliferation induced by ICT and DICT was completely antagonized by 10.(-7 )mol/L pure estrogen receptor antagonist, ICI182,780.. ICT and DICT possess estrogen-like activity of enhancing proliferation in MCF-7 and T47D cells. However, ICA appears to have no estrogenicity on MCF-7 and T47D cell lines in vitro.

Topics: Breast Neoplasms; Cell Division; Drugs, Chinese Herbal; Flavonoids; Humans; Phytoestrogens; Tumor Cells, Cultured

Although many dietary studies have focused on breast cancer risk, few have examined dietary influence on tumor characteristics such as estrogen receptor (ER) status. Because phytoestrogens may modulate hormone levels and ER expression, we analyzed ER status and phytoestrogen intake in a case-case study of 124 premenopausal breast cancer patients. We assessed intake with a food-frequency questionnaire and obtained ER status from medical records. Rather than focusing on risk, we evaluated whether low intakes were more strongly associated with ER-negative tumors than with ER-positive disease. In logistic regression adjusting for potential confounders, threefold greater risks of ER-negative tumors relative to ER-positive tumors were associated with low intake of the isoflavones genistein (odds ratio, OR=3.50; 95% confidence interval, CI=1.43-8.58) and daidzein (OR=3.10; 95% CI=1.31-7.30). Low intake of the flavonoid kaempferol (OR=0.36; 95% CI=0.16-0.83), the trace element boron (OR=0.33; 95% CI=0.13-0.83), and the phytosterol beta-sitosterol (OR=0.42; 95% CI=0.18-0.98) were associated with decreased risk of ER-negative tumors relative to ER-positive disease. Other phytoestrogens were not significantly associated with ER status. Thus, in premenopausal patients, some phytoestrogens may affect breast carcinogenesis by influencing ER status. Such findings suggest new directions for mechanistic research on dietary factors in breast carcinogenesis that may have relevance for prevention and clinical treatment.

Topics: Adult; Anticarcinogenic Agents; Boron; Breast Neoplasms; Diet; Female; Genistein; Humans; Hypolipidemic Agents; Isoflavones; Kaempferols; Middle Aged; Nutritional Status; Odds Ratio; Phytoestrogens; Premenopause; Receptors, Estrogen; Risk Factors; Sitosterols; Surveys and Questionnaires

Previous studies have compared the oestrogenic properties of phytoestrogens in a wide variety of disparate assays. Since not all phytoestrogens have been tested in each assay, this makes inter-study comparisons and ranking oestrogenic potency difficult. In this report, we have compared the oestrogen agonist and antagonist activity of eight phytoestrogens (genistein, daidzein, equol, miroestrol, deoxymiroestrol, 8-prenylnaringenin, coumestrol and resveratrol) in a range of assays all based within the same receptor and cellular context of the MCF7 human breast cancer cell line. The relative binding of each phytoestrogen to oestrogen receptor (ER) of MCF7 cytosol was calculated from the molar excess needed for 50% inhibition of 3H]oestradiol binding (IC50), and was in the order coumestrol (35x)/8-prenylnaringenin (45x)/deoxymiroestrol (50x)>miroestrol (260x)>genistein (1000x)>equol (4000x)>daidzein (not achieved: 40% inhibition at 10(4)-fold molar excess)>resveratrol (not achieved: 10% inhibition at 10(5)-fold molar excess). For cell-based assays, the rank order of potency (estimated in terms of the concentration needed to achieve a response equivalent to 50% of that found with 17beta-oestradiol (IC50)) remained very similar for all the assays whether measuring ligand ability to induce a stably transfected oestrogen-responsive ERE-CAT reporter gene, cell growth in terms of proliferation rate after 7 days or cell growth in terms of saturation density after 14 days. The IC50 values for these three assays in order were for 17beta-oestradiol (1 x 10(-11)M, 1 x 10(-11)M, 2 x 10(-11)M), and in rank order of potency for the phytoestrogens, deoxymiroestrol (1 x 10(-10)M, 3 x 10(-11)M, 2 x 10(-11)M)>miroestrol (3 x 10(-10)M, 2 x 10(-10)M, 8 x 10(-11)M)>8-prenylnaringenin (1 x 10(-9)M, 3 x 10(-10)M, 3 x 10(-10)M)>coumestrol (3 x 10(-8)M, 2 x 10(-8)M, 3 x 10(-8)M)>genistein (4 x 10(-8)M, 2 x 10(-8)M, 1 x 10(-8)M)/equol (1 x 10(-7)M, 3 x 10(-8)M, 2 x 10(-8)M)>daidzein (3 x 10(-7)M, 2 x 10(-7)M, 4 x 10(-8)M)>resveratrol (4 x 10(-6)M, not achieved, not achieved). Despite using the same receptor context of the MCF7 cells, this rank order differed from that determined from receptor binding. The most marked difference was for coumestrol and 8-prenylnaringenin which both displayed a relatively potent ability to displace [3H]oestradiol from cytosolic ER compared with their much lower activity in the cell-based assays. Albeit at varying concentrations, seven of the eight phytoe

Topics: Biological Assay; Breast Neoplasms; Cell Proliferation; Estrogen Antagonists; Estrogen Receptor Modulators; Female; Gene Expression; Genes, Reporter; Humans; Ligands; Phytoestrogens; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Tumor Cells, Cultured

Phytoestrogens have been described to be weak estrogens, SERMs or exhibit antiestrogenic properties. However, information about their activity in presence of estrogens is limited. Therefore, we have analysed the dose dependent combinatory activity of the phytoestrogens genistein (Gen), daidzein (Dai) and coumestrol (Cou), and 17beta-estradiol (E2) on cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. Neither additive nor antagonistic effects on proliferation could be observed, but in contrast all phytoestrogens possessed the ability to inhibit apoptosis in the presence of 17beta-estradiol. In summary, our in vitro results demonstrate that Gen does not exhibit any antiestrogenic properties. The additive growth stimulatory effects of Gen, Dai and Cou in the presence of E2 are not the result of a stimulation of proliferation; these phytoestrogens, at least in MCF-7 cells, could be characterised as inhibitors of apoptosis.

Topics: Apoptosis; Breast Neoplasms; Cell Proliferation; Coumestrol; Drug Interactions; Estradiol; Estrogen Antagonists; Female; Genistein; Humans; Isoflavones; Phytoestrogens

Estrogen plays a major role in breast cancer development and progression. Breast tissue and cell lines contain the necessary enzymes for estrogen synthesis, including aromatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). These enzymes can influence tissue exposure to estrogen and therefore have become targets for breast cancer treatment and prevention. This study determined whether the isoflavone genistein (GEN) and the mammalian lignans enterolactone (EL) and enterodiol (ED) would inhibit the activity of aromatase and 17beta-HSD type 1 in MCF-7 cancer cells, thereby decreasing the amount of estradiol (E2) produced and consequently cell proliferation. Results showed that 10 microM EL, ED and GEN significantly decreased the amount of estrone (E1) produced via the aromatase pathway by 37%, 81% and 70%, respectively. Regarding 17beta-HSD type 1, 50 microM EL and GEN maximally inhibited E2 production by 84% and 59%, respectively. The reduction in E1 and E2 production by EL and the reduction in E2 production by GEN were significantly related to a reduction in MCF-7 cell proliferation. 4-Hydroxyandrostene-3,17-dione (50 microM) did not inhibit aromatase but inhibited the conversion of E1 to E2 by 78%, suggesting that it is a 17beta-HSD type 1 inhibitor. In conclusion, modulation of local E2 synthesis is one potential mechanism through which ED, EL and GEN may protect against breast cancer.

Topics: 17-Hydroxysteroid Dehydrogenases; 4-Butyrolactone; Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Line, Tumor; Estradiol; Female; Genistein; Humans; Lignans; Mammals; Phytoestrogens

Dou-chi, a traditional soybean food fermented with Aspergillus sp., is usually used as a seasoning in Chinese food, and has also been used as a folk medicine in China and Taiwan. As 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavengers, four phenol compounds, one isoflavanone, eight isoflavones and one 4-pyrone have been isolated from dou-chi. Among these fourteen compounds, 3'-hydroxydaidzein, dihydrodaidzein and a 4-pyrone compound have not yet been isolated from soybean miso. The structure of the novel 4-pyrone compound, 3-((E)-2-carboxyethenyl)-5-(4-hydroxyphenyl)-4-pyrone-2-carboxylic acid was elucidated by using the same compound as that obtained from the biotransformation of daidzein. 3'-Hydroxydaidzein showed as high DPPH radical-scavenging activity as that of alpha-tocopherol, and 6-hydroxydaidzein had mushroom tyrosinase inhibitory activity with an IC(50) value of 10 muM. The order of estrogenic activity is as follows: genistein > daidzein >> 3'-hydroxydaidzein > 8-hydroxygenistein, using a green fluorescent protein expression system. Furthermore, the contents of isoflavones in the fermentation process of dou-chi were measured.

Topics: Antimutagenic Agents; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Fermentation; Free Radical Scavengers; Humans; Isoflavones; Lipoxygenase; Molecular Structure; Monophenol Monooxygenase; Phytoestrogens; Picrates; Soy Foods

Certain plant-derived compounds show selective estrogen receptor modulator (SERM) activity and may therefore be an alternative to the conventional hormone replacement therapy, which prevents osteoporosis but is also associated with an increased risk of breast and endometrial cancers. In the current study, we tested the effects of the hop-derived compounds 8-prenylnaringenin, 6-prenylnaringenin, xanthohumol and isoxanthohumol (1) to modulate markers of differentiation and gene expression in osteoblasts and (2) to regulate proliferation in MCF-7 breast cancer cells. Additionally, we analyzed the ER-binding affinities of these hop compounds as well as the ER-mediation of their effects. Bone-forming activity and ER-subtype specificity were investigated by measuring alkaline phosphatase (AP) activity in hFOB/ERalpha cells and regulation of gene transcription for AP, interleukin-6, pS2 and von Willebrand factor (VWF) in U-2 OS/ERalpha and U-2 OS/ERbeta cells. Our results demonstrate that AP, pS2 and VWF mRNA levels are significantly increased by the compounds in an estrogen-like manner via both ERalpha and ERbeta, while IL-6 is down-regulated in U-2 OS/ERalpha cells. Consistently, AP enzymatic activity is up-regulated by all compounds in hFOB/ERalpha9 cells. Depending on their concentration, all compounds show proliferative effects in MCF-7 cells. Except for 8-PN the hop constituents display an ERbeta-preference. Reversal of estrogen-specific AP-induction in Ishikawa cells indicates an ER-regulated mechanism. Finally, the flavonoids display cytotoxic effects only at high concentrations (> or =10(-4)M). In summary, we have demonstrated for the first time that specific phytoestrogen compounds found in hop extracts exert estrogen-like activities on bone metabolism. Regarding a potential for use in osteoporosis-prevention therapy, the dosage of a phytoestrogen, which is taken, will play an important role concerning a desired in vivo profile.

Topics: Adult; Alkaline Phosphatase; Animals; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Ethinyl Estradiol; Female; Humans; Humulus; Osteoblasts; Osteoporosis; Osteosarcoma; Phytoestrogens; Plant Extracts; Up-Regulation

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

Topics: Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Mutagenesis, Site-Directed; Phytoestrogens; Plasmids; Point Mutation; Recombinant Proteins; Transcriptional Activation; Transfection

The influence of dietary phytoestrogens provided by Western diets on mammographic density is not well established. Soy and soy products as source of isoflavones were found to be inversely associated with high mammographic density, a marker for breast cancer risk. Another class of phytoestrogens, the lignans, which are more frequent in Western diets, are rarely investigated. Within the European Prospective Investigation into Cancer and Nutrition cohort in Heidelberg (EPIC-Heidelberg) we explored the feasibility of mammogram collection and measurement of mammographic density in order to investigate the association between dietary phytoestrogen intake and breast density patterns. Wolfe classification was used to summarize mammographic density. Dietary habits were assessed by means of a validated food frequency questionnaire. - Out of the 505 randomly selected women, 317 (63%) returned the questionnaire and 310 (61.4%) women provided informed consent to collect mammograms. Dietary intake of seven women with dense patterns (DY) was compared with 47 women without dense patterns. A high dietary intake of fibre (p-value = 0.008) and secoisolariciresinol (p-value = 0.043) is inversely associated with non-dense breast patterns. This is also observed for a high dietary intake of soy-products (p-value = 0.004) and, in tendency, genistein (p-value = 0.069). After adjustment for energy intake and age the groups of dense and non-dense mammographic patterns were different regarding the intake of carbohydrate (p = 0.032), soy-products (p = 0.020), fibre (p = 0.046), and secoisolariciresinol (p = 0.027). - Our results suggest an inverse association between dietary lignan intake and breast density, similar to the findings for isoflavones. To our knowledge this is the first report on this association, but due to the risk of chance finding, this has to be confirmed in a study with sufficient statistical power.

Topics: Breast; Breast Neoplasms; Diet; Feeding Behavior; Female; Humans; Isoflavones; Lignans; Mammography; Middle Aged; Phytoestrogens; Pilot Projects; Risk Factors; Surveys and Questionnaires

Previous epidemiological reports have suggested that red wine intake is associated with beneficial health effects due to the ability of certain phytochemical components to exert estrogen-like activity. It has been also documented that estrogens induce the proliferation of hormone-dependent breast cancer cells by binding to and transactivating estrogen receptor (ER) alpha, which in turn interacts with responsive DNA sequences located within the promoter region of target genes. In order to provide further insight into the positive association between wine consumption and the incidence of breast carcinoma in postmenopausal women, we have evaluated the estrogenic properties of two abundant wine-derived compounds, named piceatannol (PIC) and myricetin (MYR), using as model systems the hormone-sensitive MCF7 and the endocrine-independent SKBR3 breast cancer cells. On the basis of our experimental evidence PIC and MYR may contribute to the estrogenicity of red wine since: (1) they transactivate endogenous ER alpha; (2) they activate the agonist-dependent activation function (AF) 2 of ER alpha and ER beta in the context of the Gal4 chimeric proteins; (3) they rapidly induce the nuclear immunodetection of ER alpha; (4) they regulate the expression of diverse estrogen target genes; (5) they compete with 17beta-estradiol for binding to ER alpha and ER beta; and--as a biological counterpart of the aforementioned abilities--(6) they exert stimulatory effects on the proliferation of MCF7 cells. Hence, the estrogenic activity of PIC and MYR might be considered at least as a potential factor in the association of red wine intake and breast tumors, particularly in postmenopausal women.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Flavonoids; Gene Expression Regulation; Genes, Reporter; Humans; Molecular Structure; Phenols; Phytoestrogens; Protein-Tyrosine Kinases; Recombinant Fusion Proteins; Stilbenes; Wine

Topics: Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Complementary Therapies; Culture; Estrogens; Fear; Female; Heart Diseases; Hormone Replacement Therapy; Humans; Longevity; Menopause; Middle Aged; Osteoporosis, Postmenopausal; Perimenopause; Phytoestrogens; Phytotherapy; Progestins; Risk Assessment; Women's Health

Much of the interest on the chemopreventive properties of licorice has been focused on the plant genius Glycyrrhiza glabra. In this study the ethanol extract of Chinese licorice root, Glycyrrhiza uralensis (G. uralensis) was investigated for its estrogenic effect and the ability to inhibit cell proliferation in the MCF-7 human breast cancer cell line. The extract of the root of G. uralensis was fractionated in EtOH:H(2)O (80:20) (80% ethanol). The extract exhibited estrogenic effects similar to 17beta- estradiol (E2) and induced apoptosis at the same dose level (100 microg/ml) in MCF-7 breast cancer cells, results were associated with up-regulation of tumor suppressor gene p53 and pro-apoptotic protein Bax. G. uralensis extract caused the up-regulation of p21(waf1/cip1) and down-regulation of cdk 2 and cyclin E and most significantly, induced G1 cell cycle arrest. This is the first study to show that the ethanolic extract of the root of G. uralensis has an estrogen-like activity and anti-cancer effects against MCF-7 human breast cancer cells. Whilst the use of phytoestrogens to protect against hormone-dependent cancers or as a 'natural' alternative to hormone replacement therapy remains controversial, the data in this paper support the suggestion that extracts of root of the Chinese licorice G. uralensis might be of importance in this debate.

Topics: Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Ethanol; G1 Phase; Glycyrrhiza; Humans; Phytoestrogens; Plant Extracts; Plant Roots; Receptors, Estrogen

Understanding estrogen's regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17beta-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17beta-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17beta-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17beta-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.

Topics: Animals; Antioxidants; Base Sequence; Breast Neoplasms; Cell Line, Tumor; COS Cells; Enzyme Activation; Estrogens; Female; Gene Expression; Glutathione Transferase; Humans; In Vitro Techniques; Isoflavones; Mice; Mice, Inbred C57BL; NAD(P)H Dehydrogenase (Quinone); Phytoestrogens; Plant Preparations; Receptors, Estrogen; Response Elements; Transfection

Estrogen receptors (ERs) are nuclear transcription factors that regulate gene expression in response to estrogen and estrogen-like compounds. Identification of estrogen-regulated genes in target cells is an essential step toward understanding the molecular mechanisms of estrogen action. Using cDNA microarray examinations, 19 genes were identified as induced by 17 beta-estradiol in MCF-7 cells, 10 of which have been reported previously to be estrogen responsive or to be linked with ER status. Five known estrogen-regulated genes, E2IG4, IGFBP4, SLC2A1, XBP1 and B4GALT1, and AFG3L1, responded quickly to estrogen treatment. A novel estrogen-responsive gene was identified and named EEIG1for early estrogen-induced gene 1. EEIG1 was clearly induced by 17 beta-estradiol within 2 h of treatment, and was widely responsive to a group of estrogenic compounds including natural and synthetic estrogens and estrogenic environmental compounds. EEIG1 was expressed in ER-positive but not in ER-negative breast cancer cell lines. EEIG1 expression was repressed by antiestrogens 4-OH-tamoxifen and ICI 182,780 but not by protein synthesis inhibitors cycloheximide and puromycin. These results provide evidence that some estrogenic compounds differentially enhance the transcription of estrogen-regulated genes and suggest a role for EEIG1 in estrogen action.

Topics: Breast Neoplasms; Cycloheximide; DNA-Binding Proteins; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens; Female; Fulvestrant; Galactosyltransferases; Gene Expression Regulation; Humans; Insulin-Like Growth Factor Binding Protein 4; Neoplasm Proteins; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Pesticides; Phytoestrogens; Protein Synthesis Inhibitors; Puromycin; Receptors, Estrogen; Regulatory Factor X Transcription Factors; Tamoxifen; Transcription Factors; Tumor Cells, Cultured; X-Box Binding Protein 1

Topics: Aged; Breast Neoplasms; Diet; Female; Humans; Isoflavones; Middle Aged; Netherlands; Phytoestrogens; Plant Preparations; Receptors, Estrogen

A high intake of phytoestrogens, particularly isoflavones, has been suggested to decrease breast cancer risk. Results from human studies are inconclusive.. We investigated the association between phytoestrogen intake and breast cancer risk in a large prospective study in a Dutch population with a habitually low phytoestrogen intake.. The study population consisted of 15 555 women aged 49-70 y who constituted a Dutch cohort of the European Prospective Investigation into Cancer and Nutriton (EPIC; 1993-1997). Data concerning habitual dietary intake in the preceding year were obtained by using a validated food-frequency questionnaire. The content of isoflavones and lignans in relevant food items was estimated through a literature search, the use of food-composition tables, and contact with experts. Newly diagnosed breast cancer cases up to 1 January 2001 were identified through linkage with the Comprehensive Cancer Center Middle Netherlands. Hazard ratios for the disease were estimated by Cox proportional hazard analysis for quartiles of isoflavone and lignan intake. Associations were adjusted for known breast cancer risk factors and daily energy intake.. A total of 280 women were newly diagnosed with breast cancer during follow-up. The median daily intakes of isoflavones and lignans were 0.4 (interquartile range: 0.3-0.5) and 0.7 (0.5-0.8) mg/d, respectively. Relative to the respective lowest intake quartiles, the hazard ratios for the highest intake quartiles for isoflavones and lignans were 1.0 (95% CI: 0.7, 1.5) and 0.7 (0.5, 1.1), respectively. Tests for trend were nonsignificant.. In Western populations, a high intake of isoflavones or mammalian lignans is not significantly related to breast cancer risk.

Topics: Aged; Anthropometry; Breast Neoplasms; Diet; Female; Humans; Isoflavones; Lignans; Middle Aged; Netherlands; Phytoestrogens; Plant Preparations; Postmenopause; Risk Factors; Surveys and Questionnaires

A diet high in isoflavonoids (soy) is associated with lower breast cancer risk in Asian populations. Due to the low soy intake, dietary lignans may be the more important phytoestrogen class in Western populations. We used a population-based case-control study of breast cancer by age 50 in southern Germany to evaluate the association between dietary intake of different phytoestrogens and premenopausal breast cancer risk. Dietary information was collected from 278 premenopausal cases and 666 age-matched controls, using a validated FFQ. Using multivariate logistic regression, the highest vs. lowest intake quartiles of daidzein and genistein yielded significantly reduced ORs (95% CI) for breast cancer risk of 0.62 (0.40-0.95) and 0.47 (0.29-0.74), respectively. The protective effects of daidzein and genistein were found only for hormone receptor-positive tumors. High intake of other isoflavonoids, e.g., formononetin and biochanin A, as well as the sum of isoflavonoids were not associated with a decrease in risk. Breast cancer risk significantly decreased with a high intake of the plant lignan matairesinol (OR = 0.58, 95% CI 0.37-0.94) but not secoisolariciresinol or the sum of plant lignans. However, both estimated mammalian lignans, enterodiol and enterolactone, were inversely associated with breast cancer risk, with ORs (95% CI) of 0.61 (0.39-0.98) and 0.57 (0.35-0.92), respectively. No effect was found for total phytoestrogen intake. Our results suggest an important role of dietary intake of daidzein and genistein, despite low levels, as well as of matairesinol and mammalian lignans to reduce premenopausal breast cancer risk in this study population.

Topics: Adult; Breast Neoplasms; Case-Control Studies; Female; Genistein; Humans; Isoflavones; Lignans; Middle Aged; Phytoestrogens; Plant Preparations; Premenopause; Risk

We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 micro M. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.

Topics: Arylsulfotransferase; Blood Platelets; Breast Neoplasms; Cell Line; Cerebroside-Sulfatase; Estrogens; Flavonoids; Humans; Isoflavones; Liver; Phytoestrogens; Plant Preparations; Protein Isoforms; Risk Factors; Steryl-Sulfatase; Substrate Specificity; Sulfatases; Sulfates; Sulfotransferases

There is evidence that diets which contain high levels of phytoestrogenic isoflavanoids are associated with a low incidence of osteoporosis and menopausal vasomotor symptoms. Plant extracts such as red clover, which contain high levels of isoflavanoids, have been used to reduce menopausal symptoms and have been shown to reduce bone loss in healthy women. A placebo-controlled clinical trial [ISRCTN42940165] of red clover is reported in this issue of Breast Cancer Research and shows that these phytoestrogens do not cause any oestrogenic increase in breast density, which would indicate that they are unlikely to cause an increased risk of breast cancer.

Topics: Anticarcinogenic Agents; Bone and Bones; Breast; Breast Neoplasms; Female; Hormone Replacement Therapy; Hot Flashes; Humans; Isoflavones; Menopause; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Extracts; Plant Preparations; Selective Estrogen Receptor Modulators; Thromboembolism; Trifolium

Topics: Breast Neoplasms; Female; Humans; Isoflavones; Osteoporosis; Phytoestrogens; Plant Preparations; Treatment Outcome

A growing body of evidence concerning estrogen effects cannot be explained by the classic model of hormone action, which involves the binding to estrogen receptors (ERs) alpha and ERbeta and the interaction of the steroid-receptor complex with specific DNA sequences associated with target genes. Using c-fos proto-oncogene expression as an early molecular sensor of estrogen action in ERalpha-positive MCF7 and ER-negative SKBR3 breast cancer cells, we have discovered that 17beta-estradiol (E2), and the two major phytoestrogens, genistein and quercetin, stimulate c-fos expression through ERalpha as well as through an ER-independent manner via the G protein-coupled receptor homologue GPR30. The c-fos response is repressed in GPR30-expressing SKBR3 cells transfected with an antisense oligonucleotide against GPR30 and reconstituted in GPR30-deficient MDA-MB 231 and BT-20 breast cancer cells transfected with a GPR30 expression vector. GPR30-dependent activation of ERK1/2 by E2 and phytoestrogens occurs via a Gbetagamma-associated pertussis toxin-sensitive pathway that requires both Src-related and EGF receptor tyrosine kinase activities. The ability of E2 and phytoestrogens to regulate the expression of growth-related genes such as c-fos even in the absence of ER has interesting implications for understanding breast cancer progression.

Topics: Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogen Receptor alpha; Genistein; Humans; Isoflavones; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oligoribonucleotides, Antisense; Phosphorylation; Phytoestrogens; Plant Preparations; Plasmids; Proto-Oncogene Mas; Proto-Oncogene Proteins c-fos; Quercetin; Receptors, Estrogen; Receptors, G-Protein-Coupled; RNA, Messenger; Signal Transduction; Transcriptional Activation; Transfection; Up-Regulation

While searching for new estrogenic compounds from the plant kingdom, we investigated an extract of the seeds of Cuscuta chinensis (Convolvulaceae) which showed potency for stimulating MCF-7 cell proliferation. A novel resin glycoside, cuscutic resinoside A ( 6) was isolated along with five known compounds from the extract. The structure was deduced from its spectral data as (11 S)-hydroxyhexadecanoic acid 11- O-alpha- L-(4- O-2 R,3 R-nilylrhamnopyranosyl)-(1-->2)- O-alpha- L-rhamnopyranosyl-(1,2-lactone) forming a unique 15-membered macrocyclic lactone. The compound significantly stimulated not only MCF-7 cell proliferation but also T47D human breast cancer cells at a concentration of 10 microM. Along with cuscutamine ( 1) and kaempferol ( 4), 6 was tested in the transient luciferase reporter assay and was found to have different luciferase inducing activity characteristics from the other compounds. These results suggest that 6 stimulated cancer cell proliferation by a different mechanism from 1 and 4.

Topics: Breast Neoplasms; Cell Division; Cell Line, Tumor; Cuscuta; Female; Glycolipids; Humans; Isoflavones; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Preparations; Seeds

Subjects of this study consisted of 333 women (aged 45-75 years) drawn from a large United Kingdom prospective study of diet and cancer, the European Prospective Investigation of Cancer and Nutrition-Norfolk study. Using newly developed gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry methods incorporating triply (13)C-labeled standards, seven phytoestrogens (daidzein, genistein, glycitein, O-desmethylangolensin, equol, enterodiol, and enterolactone) were measured in 114 spot urines and 97 available serum samples from women who later developed breast cancer. Results were compared with those from 219 urines and 187 serum samples from healthy controls matched by age and date of recruitment. Dietary levels were low, but even so, mean serum levels of phytoestrogens were up to 600 times greater than postmenopausal estradiol levels. Phytoestrogen concentrations in spot urine (adjusted for urinary creatinine) correlated strongly with that in serum, with Pearson correlation coefficients > 0.8. There were significant relationships (P < 0.02) between both urinary and serum concentrations of isoflavones across increasing tertiles of dietary intakes. Urinary enterodiol and enterolactone and serum enterolactone were significantly correlated with dietary fiber intake (r = 0.13-0.29). Exposure to all isoflavones was associated with increased breast cancer risk, significantly so for equol and daidzein. For a doubling of levels, odds ratios increased by 20-45% [log(2) odds ratio = 1.34 (1.06-1.70; P = 0.013) for urine equol, 1.46 (1.05-2.02; P = 0.024) for serum equol, and 1.22 (1.01-1.48; P = 0.044) for serum daidzein]. These estimates of risk are similar to those established for estrogens and androgens in postmenopausal breast cancer but need confirmation in larger studies.

Topics: Adult; Aged; Analysis of Variance; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Diet; Dietary Supplements; Humans; Incidence; Isoflavones; Middle Aged; Odds Ratio; Phytoestrogens; Plant Preparations; Probability; Prognosis; Prospective Studies; Reference Values; Registries; Risk Assessment; Sensitivity and Specificity; United Kingdom

The aim of this study was to evaluate the effects of Sedum sarmentosun Bunge (SS) on the lipid on serum and the collagen content of the connective tissues in ovariectomized estrogen-deficient rats. Three groups were surgically ovariectomized. The fourth group was sham operated. From day 2 until day 37 after the ovariectomy, Sprague-Dawley female rats were randomly assigned to the following groups: sham-operated rats (sham), ovariectomized control rats (OVX-control), ovariectomized rats supplemented with an ethyl ether fraction of SS at 10 mg/kg bw/d (OVX-EE), ovariectomized rats supplemented an ethyl acetate fraction of SS at 10 mg/kg bw/d (OVX-EA). The SS fractions were orally administrated at 1 mL per day. The estrogenic effects of the ethyl ether and ethyl acetate fractions of SS, were investigated using one in vitro assay and two in vivo assays. The treatment of the partition of the ethyl ether and ethyl acetate layers of SS increased the transcriptional activity 0.7-fold and 0.5-fold compared to those that were given 17beta-estradiol treatment, respectively. The OVX rats were significantly heavier than the sham-operated rats at all times, but supplementation with the SS extracts tended to result in less weight gain than OVX-control. The serum triglyceride levels were significantly decreased after supplementation with the SS portion EE and EA layers. Supplementation with the SS extracts prevented a decrease in the collagen level in bone and cartilage tissues. This result indicates that the SS affects the collagen synthesis in ovariectomized rats. These results are consistent with the conclusions based on the estrogenic activities of SS. Therefore, it may be used to possibly improve the quality of life in menopausal women.

Topics: Acetates; Animals; Body Weight; Breast Neoplasms; Estradiol; Ether; Female; Humans; Isoflavones; Organ Size; Ovariectomy; Phytoestrogens; Plant Extracts; Plant Preparations; Rats; Rats, Sprague-Dawley; Sedum; Triglycerides; Tumor Cells, Cultured; Uterus

Circulating hormones are associated with mammographic density, an intermediate marker of breast cancer risk. Differences in circulating hormones, including estrone and testosterone, have been observed in premenopausal women based on their capacity to metabolize daidzein, an isoflavone found predominantly in soybeans. Equol and O-desmethylangolensin (O-DMA) are products of intestinal bacterial metabolism of daidzein. There is interindividual variability in the capacity to produce daidzein metabolites; individuals can be equol producers or non-producers and O-DMA producers or non-producers. We tested the hypothesis that daidzein-metabolizing phenotypes are associated with mammographic density. Participants were recruited from among 92 sedentary, postmenopausal women, ages 50 to 75 years, who participated in a 1-year physical activity intervention. Pre-intervention mammographic density was determined using a computer-assisted, gray-scale thresholding technique. Fifty-five of these women consumed supplemental soy protein (>10 mg daidzein/d) for 3 days and collected a first-void urine sample on the fourth day to determine daidzein-metabolizing phenotypes. Equol and O-DMA concentrations were measured using gas chromatography-mass spectrometry. Associations between daidzein-metabolizing phenotypes and percent mammographic density were adjusted for age, maximum adult weight, gravidity, family history of breast cancer, and serum follicle-stimulating hormone and free testosterone concentrations. Mammographic density was 39% lower in equol producers compared with non-producers (P = 0.04). O-DMA producers had mammographic density 69% greater than non-producers (P = 0.05). These results suggest that particular intestinal bacterial profiles are associated with postmenopausal mammographic density, and these associations are not entirely explained by differences in reproductive or anthropometric characteristics or circulating hormones.

Topics: Aged; Biomarkers, Tumor; Breast; Breast Neoplasms; Cross-Sectional Studies; Dietary Supplements; Equol; Female; Gas Chromatography-Mass Spectrometry; Humans; Intestines; Isoflavones; Mammography; Middle Aged; Obesity; Phenotype; Phytoestrogens; Postmenopause; Soybean Proteins

This study investigates whether intake of phyto-oestrogens is associated with breast cancer risk in South Asian women from the Indian subcontinent, whose diet is rich in pulses and vegetables but poor in soyfoods.. A total of 240 South Asian breast cancer cases living in England and 477 age-matched population-based controls were recruited into the study. Dietary intake was measured using a validated food frequency questionnaire. Conditional logistic regression models were used to estimate the effect of phyto-oestrogen intake on breast cancer risk.. After adjustment for known breast cancer risk factors and total energy intake, there was moderate evidence of a dose-effect response in the odds of breast cancer with isoflavone intake (p-value for trend 0.08), with women in the top quartile having approximately half the odds of breast cancer of those in the bottom one (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.33, 1.00) but with no reductions in the odds for women in the second and third quartiles. The ORs for second, third and highest quartiles of total lignan intake compared to the lowest were 0.78 (95% CI 0.48, 1.26), 0.74 (0.46, 1.19) and 0.66 (0.41, 1.07), respectively, again with moderate evidence of a linear dose-effect response (p-value for trend 0.09). Further adjustment for non-startch polysaccharides (NSP) intake slightly weakened the phyto-oestrogens-breast cancer associations.. These findings are consistent with the possibility that high phyto-oestrogen intake may protect against breast cancer, but further research is required to confirm this hypothesis.

Topics: Adult; Aged; Asia, Southeastern; Breast Neoplasms; Case-Control Studies; Diet; England; Female; Humans; Middle Aged; Odds Ratio; Phytoestrogens; Risk Factors; Vegetables

Ginseng has been recommended to alleviate the menopausal symptoms, which indicates that components of ginseng very likely contain estrogenic activity. We have examined the possibility that a component of Panax ginseng, ginsenoside-Rb1, acts by binding to estrogen receptor. We have investigated the estrogenic activity of ginsenoside-Rb1 in a transient transfection system using estrogen-responsive luciferase plasmids in MCF-7 cells. Ginsenoside-Rb1 activated the transcription of the estrogen-responsive luciferase reporter gene in MCF-7 breast cancer cells at a concentration of 50 microM. Activation was inhibited by the specific estrogen receptor antagonist ICI 182,780, indicating that the estrogenic effect of ginsenoside-Rb1 is estrogen receptor dependent. Next, we evaluated the ability of ginsenoside-Rb1 to induce the estrogen-responsive gene c-fos by semi-quantitative RT-PCR assays and Western analyses. Ginsenoside-Rb1 increased c-fos both at mRNA and protein levels. However, ginsenoside-Rb1 failed to activate the glucocorticoid receptor, the retinoic acid receptor, or the androgen receptor in CV-1 cells transiently transfected with the corresponding steroid hormone receptors and hormone responsive reporter plasmids. These data support our hypothesis that ginsenoside-Rb1 acts a weak phytoestrogen, presumably by binding and activating the estrogen receptor.

Topics: Adenocarcinoma; Breast Neoplasms; Estrogens; Estrogens, Non-Steroidal; Gene Expression Regulation; Ginsenosides; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Tumor Cells, Cultured

Seven legume extracts containing phytoestrogens were analyzed for estrogenic activity. Methanol extracts were prepared from soybean (Glycine max L.), green bean (Phaseolus vulgaris L.), alfalfa sprout (Medicago sativa L.), mung bean sprout (Vigna radiata L.), kudzu root (Pueraria lobata L.), and red clover blossom and red clover sprout (Trifolium pratense L.). Extracts of kudzu root and red clover blossom showed significant competitive binding to estrogen receptor beta (ERbeta). Estrogenic activity was determined using an estrogen-dependent MCF-7 breast cancer cell proliferation assay. Kudzu root, red clover blossom and sprout, mung bean sprout, and alfalfa sprout extracts displayed increased cell proliferation above levels observed with estradiol. The pure estrogen antagonist, ICI 182,780, suppressed cell proliferation induced by the extracts, suggesting an ER-related signaling pathway was involved. The ER subtype-selective activities of legume extracts were examined using transiently transfected human embryonic kidney (HEK 293) cells. All seven of the extracts exhibited preferential agonist activity toward ERbeta. Using HPLC to collect fractions and MCF-7 cell proliferation, the active components in kudzu root extract were determined to be the isoflavones puerarin, daidzin, genistin, daidzein, and genistein. These results show that several legumes are a source of phytoestrogens with high levels of estrogenic activity.

Topics: Breast Neoplasms; Cell Division; Cell Line; Chromatography, High Pressure Liquid; Embryo, Mammalian; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Estrogens, Non-Steroidal; Fabaceae; Humans; Isoflavones; Kidney; Methanol; Phytoestrogens; Plant Extracts; Plant Preparations; Receptors, Estrogen; Transfection; Tumor Cells, Cultured

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), a steroid hormone derived from Vitamin D(3), is a negative growth regulator of breast cancer cells, and Vitamin D(3) analogs represent a novel treatment approach for human cancer. Elucidation of Vitamin D(3) receptor (VDR) regulation may reveal strategies to sensitize cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. We have previously characterized an estrogen responsive promoter region (800 bp upstream of exon 1c) in the human VDR gene, and the present studies examined regulation of this VDR promoter region by two phytoestrogens, resveratrol (present in red wine) and genistein (present in soy). We transiently transfected a VDR promoter luciferase construct into the estrogen receptor (ER) positive human breast cancer cell lines T47D and MCF-7, and treated with 0.4-4 microM resveratrol or 5-500 nM genistein. Both phytoestrogens up-regulated the transcription of the VDR promoter, as measured by reporter gene activity, approximately two-fold compared to vehicle treated cells. Co-treatment with the anti-estrogen tamoxifen (TAM) in T47D cells and transfection in an estrogen receptor negative breast cancer cell line demonstrated that the effects of phytoestrogens on the VDR promoter are dependent on estrogen receptor. Resveratrol and genistein also increased VDR protein expression as detected by Western blotting. Treatment with resveratrol had no effect on cell number or cell cycle profile, while treatment with genistein increased cell number. Because resveratrol could up-regulate VDR without increasing breast cancer cell growth, we hypothesized that resveratrol mediated increase in VDR expression would sensitize breast cancer cells to the effects of 1,25-dihydroxyvitamin D(3) and Vitamin D(3) analogs. In support of this hypothesis, both T47D and MCF-7 cells pre-treated with resveratrol exhibited increased VDR mediated transactivation of a Vitamin D(3) responsive promoter compared to cells pre-treated with vehicle. In addition, co-treatment with resveratrol enhanced the growth inhibitory effects of 1,25-dihydroxyvitamin D(3) and the Vitamin D(3) analog EB1089. These data support the concept that dietary factors, such as phytoestrogens, may impact on breast cancer cell sensitivity to Vitamin D(3) analogs through regulation of the VDR promoter.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Blotting, Western; Breast Neoplasms; Calcitriol; Cell Cycle; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Flow Cytometry; Genes, Reporter; Genistein; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Promoter Regions, Genetic; Protein Binding; Protein Structure, Tertiary; Receptors, Calcitriol; Resveratrol; Stilbenes; Tamoxifen; Time Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Tumor Cells, Cultured; Up-Regulation

Dietary genistein, a natural flavone compound found in soy, has been proposed to be related to the lower prevalence of breast cancer in Asian women. In order to elucidate the mechanism of chemopreventive effect of genistein so that to provide more scientific basis for dietary intervention for breast cancer in women, the apoptosis in estrogen responsive breast cancer cell lines (MCF-7 and T47D cells) was induced as the study model and the effect of genistein on the apoptosis was observed. The results showed that, functionally similar to the anti-estrogen tamoxifen, genistein induced in a dose- and time-dependent manner the MCF-7 cell apoptosis at concentrations above 20 x 10(-6) mol/L. The findings suggested that the increased isoflavone intake can induce apoptosis in estrogen responsive cells.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Drug; Genistein; Glycine max; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Receptors, Estrogen

Phytoestrogens are a group of compounds present in human diet that display estrogenic-like properties. Several studies have demonstrated that populations who consume large quantities of phytoestrogens have a reduced risk of estrogen-dependent cancers. Although it has been shown that certain phytoestrogens modulate estrogen action, their biological role in cancer reduction remains unclear. Through the use of differential display reverse transcriptase-polymerase chain reaction and representational difference analysis of cDNA, we have identified several phytoestrogen-responsive genes from the human breast cancer cell MCF-7. Two of these genes, PE-13.1 and pRDA-D, have been characterized in greater detail in this study. These genes were not previously known to be regulated by phytoestrogen or estradiol. PE-13.1 is a novel gene that specifies the coding of a 1.10-kb mRNA transcript. Northern blot analysis confirmed that the PE-13.1 transcript is up-regulated by phytoestrogens (Genistein, sevenfold; Zearalenone, twofold) and is nonresponsive to estradiol. Conversely, the pRDA-D transcript was down-regulated by both phytoestrogens and estradiol. The antiestrogen ICI-182,780 inhibits the expression of PE-13.1 and reverses the inhibition of pRDA-D expression induced by phytoestrogens and estradiol. Analysis of the tissue distribution of PE-13.1 transcript by RNA blot reveals that this transcript is expressed in both normal and tumor tissues. This report demonstrates for the first time the presence of two phytoestrogen-responsive genes that may be used as molecular markers in understanding the role dietary estrogen plays in cancer prevention.

Topics: Blotting, Northern; Breast Neoplasms; Estrogens, Non-Steroidal; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Genistein; Humans; Isoflavones; Oligonucleotide Array Sequence Analysis; Phytoestrogens; Plant Preparations; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured; Zearalenone

The proliferative effects of thirty Oriental medicinal herbs on MCF-7 (estrogen-sensitive breast cancer cell line) and ROS 17/2.8 osteoblast-like cells were determined using the MTT assay. Methanol extracts from several herbs was found to show proliferative activity on the above two cell lines in the range of 5 to 100 microg/mL. Among these active herbs, the methanol extract from the rhizomes of Drynaria fortunei showed the most potent proliferative activity, and the cell proliferations were significantly increase by 136 and 158% in the MCF-7 and ROS 17/2.8 cells, respectively, when treated with 100 microg/mL. Through a bioassay-guided separation, eight flavonoids, including four new flavan-3-ols and two propelargonidins, together with the known (-)-epiafzelechin and naringin, were isolated. Their chemical structures were characterized as (-)-epiafzelechin (1), (-)-epiafzelechin-3-O-beta-D-allopyranoside (2), (-)-epiafzelechin-3-O-(6"-O-acetyl)-beta-D-allopyranoside (3), 4beta-carboxymethyl-(-)-epiafzelechin methyl ester (4), 4beta-carboxymethyl-(-)-epiafzelechin sodium salt (5), naringin (6), (-)-epiafzelechin-(4beta-->8)-4beta-carboxymethylepiafzelechin methyl ester (7) and (-)epiafzelechin-(4beta-->8, 2beta-->O-->7)-epiafzelechin-(4beta-->8)-epiafzelechin (8) by extensive 1D and 2D NMR spectroscopy. Most of these flavonoids, in the range of 10(-15) to approximately 10(-6) M, accelerated the proliferation of MCF-7 cell, with compounds 7 and 8, in the range of 10(-15) to approximately 10(-12) M, showing especially potent proliferation effects. Meanwhile, seven flavonoids, with the exception of compound 4, stimulated the proliferation of ROS 17/2.8 cells in the range of 10(-15) to approximately 10(-6) M, with compounds 5-8 especially accelerating the proliferation, in dose-dependent manners (10(-15) to approximately 10(-9) M), and their proliferative effect was much stronger than that of E2 and genistein. These results suggest that propelargonidin dimers and trimers isolated from the rhizomes of Drynaria fortunei may be useful as potential phytoestrogens, which play important physiological roles in the prevention of postmenopausal osteoporosis.

Topics: Animals; Breast Neoplasms; Cell Division; Drugs, Chinese Herbal; Flavonoids; Humans; Isoflavones; Magnetic Resonance Spectroscopy; Molecular Structure; Osteoblastoma; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Polypodiaceae; Rats; Rhizome; Tumor Cells, Cultured

Ginsenosides have demonstrated pharmacological effects in the central nervous, cardiovascular, and endocrine systems. We hypothesize that ginsenosides might mediate some of their actions by binding to the estrogen receptor, as they share many of the protective actions of estrogen in various physiological systems. The present study is aimed to determine whether ginsenoside Rg1 can act like an estrogen analog in stimulating human breast cancer cell growth as well as in the activation of estrogen response element-luciferase activity in HeLa cell. Rg1, but not its aglycone, stimulates [methyl-(3)H] thymidine incorporation in estrogen receptor-positive MCF-7 in a dose-dependent manner (10(-15)-10(-7) M). The stimulation of MCF-7 cell proliferation by 3 x 10(-13) M Rg1 can be blocked by 10(-6) M of the estrogen antagonist ICI 182780. Moreover, Rg1 stimulates estrogen response element-luciferase reporter gene activity in HeLa cells with an optimal dose of 3 x 10(-10) M. Such stimulation can also be blocked by 10(-6) M ICI 182780. In addition, Rg1 has no effect on [methyl-(3)H]thymidine incorporation in estrogen receptor-negative human breast cancer cells (MDA-MB-231). Furthermore, Rg1 failed to displace the specific binding of [(3)H]17 beta-estradiol to MCF-7 cell lysates, suggesting that no direct interaction of Rg1 with estrogen receptor is needed for its estrogenic action. Our results indicate that ginsenosides Rg1 has estrogen-like activity and should be classified as a novel class of potent phytoestrogen.

Topics: Breast Neoplasms; Central Nervous System Agents; Drugs, Chinese Herbal; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Ginsenosides; HeLa Cells; Humans; Isoflavones; Luciferases; Panax; Phytoestrogens; Plant Preparations; Radioligand Assay; Receptors, Estrogen; Saponins; Thymidine; Tritium; Tumor Cells, Cultured

Although the majority of ecological and experimental studies have suggested a potential role of phytoestrogens in breast cancer prevention, findings from epidemiological studies have been inconsistent. Part of the inconsistencies may be attributable to the difficulty in measuring intake levels of phytoestrogens. Overnight urine samples from 250 incident breast cancer cases and their individually matched controls were analyzed for urinary excretion rates of isoflavonoids, mammalian lignans, and citrus flavonoids. The study subjects were a subset of the participants in the Shanghai Breast Cancer Study, a large population-based case-control study conducted in Shanghai from 1996-1998. To minimize potential influence of treatment on the exposure of interest, urine samples from breast cancer cases were collected before cancer therapy. Urinary excretion of total isoflavonoids and mammalian lignans was substantially lower in breast cancer cases than in controls. The median excretion rate of total isoflavonoids was 13.97 nmol/mg creatinine in cases and 23.09 in controls (P = 0.01), and the median excretion rate of total lignans was 1.77 in cases and 4.16 in controls (P < 0.01). The risk of breast cancer was reduced with increasing excretion of total isoflavonoids (P for trend, 0.04) and total lignans (P for trend, <0.01), with adjusted odds ratios of 0.62 (95% confidence interval, 0.39-0.99) and 0.40 (95% confidence interval, 0.24-0.64) observed for the highest versus the lowest tertile of total isoflavonoid and lignan excretion, respectively. The adjusted odds ratio was 0.28 (95% confidence interval, 0.15-0.50) for women who had a high excretion rate of both total lignans and isoflavonoids compared with those with a low excretion of both groups of phytoestrogens. No association was observed with citrus flavonoids. The results from this study suggest that high intake of certain phytoestrogens may reduce the risk of breast cancer.

Topics: Adult; Breast Neoplasms; Case-Control Studies; China; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Lignans; Middle Aged; Odds Ratio; Phytoestrogens; Plant Preparations; Risk Factors

Asian individuals have much lower incidences of prostate and breast cancer than populations from Western developed countries. They also consume a lower fat, higher fiber diet, with a large intake of phytoestrogens. These phytoestrogens may protect against hormone-dependent cancers and other diseases. Our study used established gas chromatography-mass spectrometry (GC-MS) methodologies to measure the concentrations of four phytoestrogens (daidzein, genistein, equol and enterolactone) in serum samples obtained from Japanese men (n = 102) and women (n = 125) > 40 y old. The results were compared with those obtained with samples from the UK. The Japanese men and women had higher (P < 0.001) concentrations of circulating daidzein, genistein and equol than individuals from the UK. The mean concentration of genistein in Japanese men, for example, was 492.7 nmol/L, compared with 33.2 nmol/L in men from the UK. The two populations, however, had similar serum concentrations of enterolactone. Furthermore, 58% of the Japanese men and 38% of the Japanese women had equol concentrations > 20 nmol/L, compared with none of the UK men and 2.2% of the UK women. These results support previously published GC-MS results from studies with low numbers of samples.

Topics: 4-Butyrolactone; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Chromans; Diet; Equol; Estrogens, Non-Steroidal; Female; Gas Chromatography-Mass Spectrometry; Genistein; Humans; Isoflavones; Japan; Lignans; Male; Middle Aged; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; United Kingdom

Two soy sapogenols, soyasapogenol A (SA) and soyasapogenol B (SB) were tested for their estrogenic activities in estrogen responsive MCF-7 or estrogen-insensitive MDA-MB-231 (MDA) human breast cancer cells. SB and SA had differential actives on cell proliferation with 10 microM SB being growth inhibitory to MDA cells with no significant effect at any concentration on MCF-7 cells. SA also inhibited MDA cell proliferation at 10 micro, but at this same dose stimulated a 2.5-fold increase in MCF-7 proliferation. SA (0.1-10 microM) induced pS2 mRNA levels and the induction was blocked by co-treatment of cells with the anti-estrogen ICI 182,780. SA also induced the formation of an ER-ERE DNA complex measured by electrophoretic mobility shift assay. In summary, these results show that soyasapogenol A is estrogenic, whereas soyasapogenol B is growth inhibitory.

Topics: Blotting, Northern; Breast Neoplasms; Cell Division; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Female; Fulvestrant; Gene Expression; Glycine max; Humans; Isoflavones; Oleanolic Acid; Phytoestrogens; Plant Extracts; Plant Preparations; Receptors, Estrogen; RNA, Messenger; Saponins; Tumor Cells, Cultured

Flavonoids, such as daidzein and genistein, present in dietary plants like soybean, have unique chemical properties with biological activity relevant to cancer. Many flavonoids and polyphenols, including resveratrol in red wine and epigallocatechin gallate in green tea, are known antioxidants. Some of these compounds have estrogenic (and antiestrogenic) activity and are commonly referred to as phytoestrogens. A yeast-based estrogen receptor (ER) reporter assay has been used to measure the ability of flavonoids to bind to ER and activate estrogen responsive genes. Recently, estrogenic compounds were also shown to trigger rapid, nongenomic effects. The molecular mechanisms, however, have not been completely detailed and little information exists regarding their relevance to cancer progression. As a preliminary step toward elucidating rapid phytoestrogen action on breast cancer cells, we investigated the effect of 17-beta estradiol (E2), genistein, daidzein and resveratrol on the activation status of signaling proteins that regulate cell survival and invasion, the cell properties underlying breast cancer progression. The effect of these estrogenic compounds on the activation, via phosphorylation, of Akt/protein kinase B (Akt) and focal adhesion kinase (FAK) were analyzed in ER-positive and -negative human breast cancer cell lines. E2, genistein and daidzein increased whereas resveratrol decreased both Akt and FAK phosphorylation in nonmetastatic ER-positive T47D cells. In metastatic ER-negative MDA-MB-231 cells, all estrogenic compounds tested increased Akt and FAK phosphorylation. The inhibitory action of resveratrol on cell survival and proliferation is ER dependent. Therefore, all estrogenic compounds tested, including resveratrol, may exert supplementary ER-independent nongenomic effects on cell survival and migration in breast cancer cells.

Topics: Breast Neoplasms; Cell Division; Cell Survival; Enzyme Activation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens, Non-Steroidal; Flavonoids; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Genistein; Humans; Isoflavones; Phosphorylation; Phytoestrogens; Plant Preparations; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Estrogen; Resveratrol; Stilbenes; Tumor Cells, Cultured

A wide range of chemicals derived from plant and human-made xenobiotics are reported to have hormonal activities. The present study was performed to examine the estrogenic effect of Kwao Keur, Pueraria mirifica (PM), that has been used as a rejuvenating folk medicine in Thailand, using recombinant yeast, MCF-7 cell proliferation and HepG2 cell transient transfection assay. In recombinant yeast assay, 0.025, 0.25, 2.5, 25, 2.5 x 10(2), 2.5 x 10(3), 2.5 x 10(4) ng/ml concentrations of PM did not show any estrogenic activities, while 10(-9) of 17 beta-estradiol (positive control) showed high estrogenic activity. Estrogenic activities were induced at 2.5 ng/ml to 25 microg/ml concentrations of PM in a dose-dependent manner on MCF-7 cells and the estrogenic effect of PM was blocked by tamoxifen treatment, a well-known anti-estrogen. PM also showed estrogenic effect on human hepatoma cell line, HepG2 cells, containing estrogen receptor and luciferase reporter gene. Taken together, PM in itself may have no estrogenicity in yeast system, but it has estrogenicity in MCF-7 & HepG2 cells that have human metabolic enzymes. The results indicated that PM may require metabolic activation for estrogenic activity.

Topics: Biotransformation; Breast Neoplasms; Cell Division; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Humans; Isoflavones; Phytoestrogens; Plant Extracts; Plant Preparations; Plants, Medicinal; Pueraria; Receptors, Estrogen; Saccharomyces cerevisiae; Transfection; Tumor Cells, Cultured

Topics: Anticarcinogenic Agents; Breast Neoplasms; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Hot Flashes; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Soybean Proteins; Tamoxifen

The role of diet in the etiology of breast carcinoma has been debated for decades. The ecologic approach generally finds that dietary fat is highly associated with breast carcinoma mortality, with fish intake and solar ultraviolet-B (UV-B) radiation, a source of vitamin D, inversely associated. Case-control and cohort studies generally find a variety of chemical, nonfat dietary, environmental, genetic, lifestyle, and reproductive factors to be important.. An ecologic study was conducted using breast carcinoma mortality rates (1989-1996), dietary supply data, and latitude (an index of solar UV-B radiation) from 35 countries.. The fraction of energy derived from animal products (risk) combined with that from vegetable products (risk reduction), followed by solar UV-B radiation and, to a lesser extent, energy derived from alcohol (risk) and fish intake (risk reduction), were found to explain 80% of the variance of breast carcinoma mortality rates. Dietary fat contributed insignificantly in regressions involving the other factors.. It is hypothesized that animal products are associated with risk for breast carcinoma because they are associated with greater amounts of insulin-like growth factor-1 and lifetime doses of estrogen. Vegetable products contain several risk reduction components including antioxidants and phytoestrogens. The association with latitude is very likely because of solar UV-B radiation and vitamin D. Alcohol modulates estrogen's effects on breasts. Fish intake is associated with risk reduction through vitamin D and n-3 oils. These results are consistent with those of many case-control and cohort studies but should be assessed in well designed cohort studies.

Topics: Alcohol Drinking; Antioxidants; Breast Neoplasms; Diet; Ecology; Environmental Exposure; Estrogens; Estrogens, Non-Steroidal; Global Health; Humans; Insulin-Like Growth Factor I; Isoflavones; Linear Models; Meat; Phytoestrogens; Plant Preparations; Risk Factors; Seafood; Ultraviolet Rays; Vegetables

Topics: Breast Neoplasms; Diet; Dietary Supplements; Estrogens; Estrogens, Non-Steroidal; Growth Substances; Hormone Replacement Therapy; Humans; Isoflavones; Molecular Structure; Phytoestrogens; Plant Preparations; Receptors, Estrogen

Topics: Aluminum; Alzheimer Disease; Breast Neoplasms; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens, Non-Steroidal; Female; Food Contamination; Glycine max; Humans; Infertility, Male; Isoflavones; Male; Menarche; Phytoestrogens; Plant Preparations; Sperm Count

The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay is a widely used screening method to measure cell viability and proliferation. When testing the effects of kaempferol on breast cancer cell number (crystal violet staining) and viability (MTT tetrazolium assay) conflicting results were obtained. Cell number decreased but MTT formazan formation increased, suggesting a direct interaction of kaempferol with the MTT tetrazolium reduction. Direct reductive potential was observed in a cell-free system for the presumptive phytoestrogens kaempferol and resveratrol, and extracts of Hypericum perforatum L. and Cimicifuga racemosa L. All agents led to instantaneous dark blue formazan formation in the absence of cells. Additionally, antioxidants such as ascorbic acid, vitamin E and N-acetylcysteine interfered with the MTT tetrazolium assay. When MCF7 and HS578 cells treated with kaempferol were washed before addition of MTT tetrazolium, the direct reduction of dye was reduced significantly. These results indicate that the MTT tetrazolium assay may lead to false positive results when testing natural compounds with intrinsic reductive potential.

Topics: Acetylcysteine; Antioxidants; Ascorbic Acid; Breast Neoplasms; Cell Division; Cell Survival; Drug Interactions; Estrogens, Non-Steroidal; Flavonoids; Humans; Isoflavones; Kaempferols; Phytoestrogens; Plant Extracts; Plant Preparations; Plants; Quercetin; Resveratrol; Stilbenes; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured; Vitamin E

To improve E-screen assay and make it more accurate to screen estrogenic compounds.. Estrogen receptor antisense RNA expression plasmid (pCASER) was constructed and introduced into MCF-7 with lipofectAMINE(TM), and positive clones were screened out with G418. PCR amplification was employed to identify whether estrogen receptor (ER) cDNA fragment had been inserted into MCF-7 cell genomes. Western blot was applied to detect the expression of ER. Cell growth was determined by MTT assay.. One ER antisense clone (MTASER) had been screened out. The effects of 17beta-estradiol, genistein, droloxifen, miyabenol C, and kobophenol A on MCF-7 were stronger than those effects on MTASER. Epidermal growth factor (EGF) had equivalent stimulatory effects on the proliferation of MCF-7 and MTASER.. The improved E-screen assay could screen estrogenic compounds more accurately than original E-screen assay did.

Topics: Breast Neoplasms; Cell Division; Drug Evaluation, Preclinical; Estradiol; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Receptors, Estrogen; RNA, Antisense; Tumor Cells, Cultured

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Glycine max; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon PII-containing transcripts were translated more effectively than were exon I.3-containing transcripts. An understanding of the molecular mechanisms of aromatase expression between noncancerous and cancerous breast tissue, at both transcriptional and translational levels, may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissue.

Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Estrogens, Non-Steroidal; Female; Fruit; Gene Expression Regulation; Gene Silencing; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Preventive Medicine; Vegetables

The 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5) is involved in estrogen and androgen metabolism. In our study we tested the influence of environmental hormones, such as phytoestrogens (flavonoids, coumarins, coumestans), on reductive and oxidative 17beta-HSD activity of the human 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5). These dietary substances were shown to be potent inhibitors of aromatase, different 17beta-HSDs and seem to play an important role in delay of development of hormone dependent cancers. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many dietary compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among the group of flavones inhibitor potency is growing with increasing number of hydroxylations. We suggest that these substances are bound to the hydrophilic cofactor-binding pocket of the enzyme. An interesting inhibition pattern is observed for 18beta-glycyrrhetinic acid, which has no influence on the oxidative but only on the reductive reaction. This indicates that this substrate binds to pH- and cofactor-depending sites at the active center of the enzyme.

Topics: 17-Hydroxysteroid Dehydrogenases; Aromatase Inhibitors; Binding Sites; Breast Neoplasms; Coumestrol; Diet; Enzyme Inhibitors; Estrogens; Estrogens, Non-Steroidal; Female; Gene Expression; Genistein; Glycine max; Glycyrrhetinic Acid; Humans; Hydrogen-Ion Concentration; Hydroxylation; Isoenzymes; Isoflavones; Male; Models, Molecular; Oxidation-Reduction; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Quercetin; Recombinant Proteins; Testosterone; Zearalenone

An integrated QSAR model has been formulated to predict estrogenic, carcinogenic, and cancer protective effects of phytoestrogens (PE). Relative binding of PEs to estrogen receptors ER alpha and ER beta exhibited a parabolic relationship with dipole moment (mu). The high-affinity binding of PEs to ER alpha correlated with Dif0 (0 chi-0 chi v difference index encoding nonsigma electronic charge), while the low-affinity binding of PEs to ER alpha correlated with H bonding (positive coefficient) and % hydrophilic surface (negative coefficient). The high-affinity binding of PEs to ER beta correlated with molecular with (MWd) and Dif0, while the low-affinity binding of PEs to ER beta correlated with H bonding (positive coefficient) and hydrophilic-lipophilic balance (negative coefficient). Thus an increase in electronic or ionic charge, formation of H bonds, or a decrease in hydrophilic property of PEs may increase their binding to ER. The relative transcription activity (RTA) of ER alpha correlated with Dif0-Dif1, while RTA of ER beta correlated with H bonding and polarity. The PE-induced stimulation of DNA synthesis in estrogen-sensitive breast cancer (BC) cells correlated positively with (MD*4 chi v) where MD is molecular depth and 4 chi v is the valence of a 4th order fragment. IC50 for PE-induced inhibition of DNA synthesis in estrogen-sensitive BC cells correlated with (MD*Log P) and Dif3 (3 chi-3 chi v difference index encoding nonsigma electronic charge of fragments consisting of four atoms and three bonds) and Dif3(2). IC50 for PE-induced inhibition of DNA synthesis in estrogen-independent cancer cell lines correlated with (MD*Log P) and 1/water solubility. Thus molecular shape and molecular connectivity of PEs play a key role in modulating estrogen-induced transactivation activity and DNA synthesis in BC cells.

Topics: Amino Acid Sequence; Animals; Anticarcinogenic Agents; Breast Neoplasms; Carcinogens; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Molecular Sequence Data; Neoplasms; Phytoestrogens; Plant Preparations; Quantitative Structure-Activity Relationship; Rats; Receptors, Estrogen; Sequence Alignment; Sequence Homology, Amino Acid

Phytoestrogens are defined as plant substances that are structurally or functionally similar to estradiol. We report the associations of two major phytoestrogens, genistein and enterolactone, with breast cancer risk, using urinary specimens collected 1-9 years before breast cancer was diagnosed. The subjects were 88 breast cancer cases and 268 controls, selected from a cohort of postmenopausal women (n = 14,697) who participated in a breast cancer screening program. Mean levels of urinary genistein and enterolactone were determined by time resolved fluoroimmunoassay, using an average of two overnight urinary samples obtained from each participant on the first and the second screening rounds with a time interval of approximately 1 year. Odds ratios (ORs) of the highest to the lowest tertile of urinary phytoestrogen/creatinine concentrations and 95% confidence intervals (CIs) were computed. Higher urinary genistein excretion was weakly and nonsignificantly associated with a reduced breast cancer risk. OR for the highest tertile compared with lowest tertile was 0.83; 95% CI, 0.46-1.51. Higher urinary enterolactone excretion was weakly and nonsignificantly associated with an increased breast cancer risk. OR for the highest tertile compared with the lowest tertile was 1.43; 95% CI, 0.79-2.59. Tests for trends for both phytoestrogens were nonsignificant. We were not able to detect the previously reported protective effects of genistein and enterolactone on breast cancer risk in our postmenopausal population of Dutch women. Such an effect may be smaller than expected and/or limited to specific subgroups of the population.

Topics: 4-Butyrolactone; Aged; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Cohort Studies; Confidence Intervals; Estrogens, Non-Steroidal; Female; Fluoroimmunoassay; Genetic Predisposition to Disease; Genistein; Humans; Isoflavones; Lignans; Logistic Models; Mass Screening; Middle Aged; Netherlands; Odds Ratio; Phytoestrogens; Plant Preparations; Postmenopause; Predictive Value of Tests; Reference Values; Risk Assessment; Risk Factors; Sensitivity and Specificity

The estrogenicity of Black Cohosh (Cimicifuga racemosa, CR) was tested in vivo and in vitro and its effect on estrogen receptor (ER) level of human breast cancer MCF-7 cells were investigated. Based on the body weight of animals, 75, 150 and 300 mg/kg of CR were administered by tube feeding to immature female mice for 14 days. Estrus was observed and the uterine and ovary weights of mice were measured. The optimal dose of CR for the growth of MCF-7 cells was screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Subsequently, Growth curves of MCF-7 cells in blank control, 4.75 micrograms/L of CR and 0.3 nmol/L of 17 beta-estradiol groups were observed for 5 days. ER level in MCF-7 cells was analyzed by indirect immunofluorescence assay in flow cytometry. The results showed that uterine weight increased with the increasing dosage of CR and the days of estrus was significantly prolonged in the 300 mg/kg group (P < 0.05). The concentration of CR at 4.75 micrograms/L showed the strongest enhancement effects (64.7%). The doubling time (TD) of cell growth in CR group and 17 beta-estradiol group were 32.1 h and 31.7 h respectively, which were shorter than that of blank control (TD = 35.3 h). Additionally, 4.75 micrograms/L of CR significantly increased ER levels compared with the blank control (P < 0.01). Taking all the results together, CR has an estrogen-like action. The enhancing effect of CR on ER level is one of the potential mechanisms involved with its therapeutic role in climacteric syndrome.

Topics: Animals; Breast Neoplasms; Cell Division; Cimicifuga; Drugs, Chinese Herbal; Estrogens, Non-Steroidal; Humans; Isoflavones; Mice; Phytoestrogens; Plant Preparations; Plants, Medicinal; Receptors, Estrogen; Tumor Cells, Cultured

Phytoestrogens are natural constituents of our diets that have been suggested to protect against hormone-dependent breast cancer. Some of the diverse effects of these compounds may be attributed to ligand-dependent differences in their interaction with oestrogen receptor sub-classes. However, phytoestrogens can also inhibit enzymes that are involved in the generation and removal of endogenous steroid hormones. Among the most potent effects of dietary phytoestrogens is their ability to inhibit the sulphotransferases that sulphate both oestrogenic steroids and a variety of environmental chemicals, including dietary pro-carcinogens. Circulating steroid sulphates are thought to be the major source of oestradiol in post-menopausal breast tumours and sulphation is a key step in the activation of some dietary pro-carcinogens. Hence the inhibition of sulphotransferases by dietary phytoestrogens may have complex effects upon human susceptibility to breast cancer.

Topics: 3-Hydroxysteroid Dehydrogenases; Aromatase; Aromatase Inhibitors; Arylsulfatases; Blood Platelets; Breast Neoplasms; Diet; Disease Susceptibility; Estrogens; Estrogens, Non-Steroidal; Female; Flavonoids; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Steryl-Sulfatase; Sulfotransferases

Phytoestrogens are a chemically diverse group of compounds made by plants that can have estrogenic effects in animals. Both tumorigenic and antitumorigenic effects have been reported. Although estrogens stimulate the growth of many breast tumors, there is a negative correlation between the incidence of breast cancer and the phytoestrogen-rich diet of certain Asian populations. To begin to resolve this paradox, we have analyzed the estrogenic properties of genistein and quercetin, two flavonoid phytoestrogens particularly abundant in soybeans. Trans-activation experiments with a transfected reporter gene for nuclear estrogen receptors (ER) show strong activation of the endogenous ER alpha by both phytoestrogens in two MCF7 human breast cancer cell lines. This is supported by the observation that the two phytoestrogens induce the down-regulation of ER alpha mRNA and protein levels. Using chimeric proteins consisting of the hormone binding domains of ER alpha and ER beta fused to the Gal4 DNA binding domain, we have established that genistein and quercetin are full estrogenic agonists of both ER isoforms. Ligand binding experiments with purified ER alpha and ER beta confirm that the two phytoestrogens are ER ligands. At concentrations that are sufficient to obtain substantial transcriptional activity, they stimulate the proliferation of two ER alpha-dependent breast cancer cell lines. At high concentrations, such as those reached with a soy-rich diet, genistein and quercetin are strong cytotoxic agents that even kill ER-independent HeLa cells. Thus, the mode of action of phytoestrogens and the balance between being risk or chemopreventive factors for breast cancer may depend on the dietary load.

Topics: Breast Neoplasms; Cell Division; Dose-Response Relationship, Drug; Down-Regulation; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens, Non-Steroidal; Genistein; Humans; Isoflavones; Ligands; Phytoestrogens; Plant Preparations; Proteins; Quercetin; Receptors, Estrogen; RNA, Messenger; Transcription, Genetic; Trefoil Factor-1; Tumor Cells, Cultured; Tumor Suppressor Proteins; Up-Regulation

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, the expression of aromatase is upregulated compared to surrounding non-cancerous tissue. In this study, we found that wine contains phytochemicals that are capable of suppressing aromatase. Red wine was shown to be much more effective than white wine in the suppression of aromatase activity. Whole wine, lyophilized wine, and heat-treated extracts were examined for aromatase inhibition in a human placenta microsomal assay. C18 Sep-Pak cartridge (Waters Co.) separation of red wine extracts under an increasing acetonitrile (ACN) gradient found that the most active components were in the 20% ACN fraction, in that they inhibited the wild-type human placenta aromatase, wild-type porcine placenta and blastocyst aromatase in a dose-dependent fashion. The 20% ACN active fraction was heat stable and inhibited aromatase in a non-competitive manner. The aromatase-inhibitory action of red wine extracts was also examined with a transgenic mouse model in which aromatase is over-expressed in the mammary tissues. It was found that the intake of the 20% ACN fraction by gavage completely abrogated aromatase-induced hyperplasia and other changes in the mammary tissue. This is the first report demonstrating that wine, especially red wine, contains phytochemicals that can inhibit aromatase.

Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Culture Techniques; Dose-Response Relationship, Drug; Estrogens, Non-Steroidal; Female; Flavonoids; Humans; Isoflavones; Mice; Mice, Transgenic; Phytoestrogens; Placenta; Plant Preparations; Swine; Up-Regulation; Wine

Research on the relation between phytoestrogens and breast cancer risk has been limited in scope. Most epidemiologic studies have involved Asian women and have examined the effects of traditional soy foods (e.g., tofu), soy protein, or urinary excretion of phytoestrogens. The present study extends this research by examining the effects of a spectrum of phytoestrogenic compounds on breast cancer risk in non-Asian US women. African-American, Latina, and White women aged 35-79 years, who were diagnosed with breast cancer between 1995 and 1998, were compared with women selected from the general population via random digit dialing. Interviews were conducted with 1,326 cases and 1,657 controls. Usual intake of specific phytoestrogenic compounds was assessed via a food frequency questionnaire and a newly developed nutrient database. Phytoestrogen intake was not associated with breast cancer risk (odds ratio = 1.0, 95% confidence interval: 0.80, 1.3 for the highest vs. lowest quartile). Results were similar for pre- and postmenopausal women, for women in each ethnic group, and for all seven phytoestrogenic compounds studied. Phytoestrogens appear to have little effect on breast cancer risk at the levels commonly consumed by non-Asian US women: an average intake equivalent to less than one serving of tofu per week.

Topics: Adult; Aged; Black or African American; Breast Neoplasms; Case-Control Studies; Estrogens, Non-Steroidal; Feeding Behavior; Female; Hispanic or Latino; Humans; Isoflavones; Logistic Models; Middle Aged; Phytoestrogens; Plant Preparations; Plants; Risk Factors; San Francisco; White People

Topics: Breast Neoplasms; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations

Licorice root extract and its major isoflavan, glabridin, exhibited varying degrees of estrogen receptor (ER) agonism in different tissues in vitro and in vivo. Animals fed with licorice extract, compared with estradiol and glabridin, showed an increase in creatine kinase (CK) activity, a known marker for estrogen responsive genes, which was higher than expected from the levels of glabridin in the extract. This led us to test for other components that may contribute to this strong estrogen agonist activity. Results indicated that glabrene and isoliquiritigenin, (2',4',4-three hydroxy chalcone) (ILC) in the licorice extract can bind to the human ER with higher affinity (IC50, 1 and 0.5 microM) than glabridin (IC50, 5 microM). The stimulatory effects of glabrene in vivo were tissue specific and similar to those of estradiol. The effect of increasing concentrations of glabrene and ILC on the growth of breast tumor cell were biphasic. Both showed an ER-dependent growth-promoting effect at low concentrations (10 nM-10 microM), and ER-independent antiproliferative activity at concentrations >15 microM. This is the first study to indicate that glabrene, an isoflavene exerted varying degrees of ER agonism in different tissues.

Topics: Animals; Breast Neoplasms; Cell Division; Estradiol; Estrogen Receptor Modulators; Estrogens, Non-Steroidal; Female; Glycyrrhiza; HeLa Cells; Humans; Isoflavones; Organ Specificity; Phenols; Phytoestrogens; Phytotherapy; Plant Preparations; Rats; Rats, Wistar; Receptors, Estrogen; Tamoxifen; Transcription, Genetic; Tumor Cells, Cultured

The E-cadherin/catenin complex is a powerful invasion suppressor in epithelial cells. It is expressed in the human MCF-7 breast cancer cell line family, but functionally defective in the invasive MCF-7/6 variant. Previous experiments have shown that IGF-I, tamoxifen, retinoic acid and tangeretin are able to upregulate the function of this complex in MCF-7/6 cells. We investigated the effect of 8-prenylnaringenin (8-PN), the phytoestrogen present in hops and beer, on aggregation, growth and invasion in MCF-7/6 cells. 8-PN was found to stimulate E-cadherin-dependent aggregation and growth of MCF-7/6 cells in suspension. These effects could be inhibited by the pure anti-estrogen ICI 182,780. 8-PN did not affect invasion of MCF-7/6 cells in the chick heart assay in vitro. In all these aspects 8-PN mimics the effects of 17beta-estradiol on MCF-7/6 cells.

Topics: Beer; Breast Neoplasms; Cadherins; Cell Adhesion; Cell Aggregation; Estrogens, Non-Steroidal; Female; Flavanones; Flavonoids; Humans; Humulus; Isoflavones; Phytoestrogens; Plant Preparations; Tumor Cells, Cultured; Tumor Stem Cell Assay; Up-Regulation

Approximately 60% of breast cancer patients have hormone-dependent breast cancer containing estrogen receptors and requiring estrogen for tumor growth. The extent of estrogen biosynthesis and metabolism in the breast cancer tissue microenvironment influences breast-tumor development and growth, and endogenous and exogenous agents may alter the levels of hormonally active estrogens and their metabolites. Isoflavonoid phytoestrogens such as genistein exhibit numerous biochemical activities; however, their effects on estrogen biosynthesis and metabolism in breast cancer cells have not been fully examined. MCF-7 cells (hormone-dependent) and MBA-MB-231 cells (hormone-independent) were treated with genistein (100 nM) for five days and then incubated with radiolabeled estradiol (100 nM, 2.5 microCi) for 0 to 48 h. Media were extracted with ethyl acetate, and the organic residues analyzed by reverse-phase HPLC with a radioactivity flow detector. The major metabolite formed in all cases is estrone, although differences were observed between the cell lines and the various drug treatments. The formation of estrone in untreated MCF-7 cells (approximately 9.3% of radioactivity at 24 h) is relatively limited, in contrast to untreated MDA-MB-231 cells (approximately 32.0% of radioactivity at 24 h). Treatment of MCF-7 cells with 100 nM genistein increased the conversion of estradiol to estrone up to 19.5% in 24 h. The effect of genistein on estrone formation in MDA-MB-231 cells resulted in 37.7% of the radioactivity being estrone. Thus, genistein treatment of breast cancer cells resulted in increased 17-betahydroxysteroid dehydrogenase activity and elevated formation of estrone. Increased levels of oxidative 17-betahydroxysteroid dehydrogenase activity (Type II) were confirmed by Western blots. Therefore, exposure of breast cancer cells to genistein results in elevated conversion of estradiol to estrogenically weaker or inactive metabolites. The regulation of breast-tissue aromatase by exogenous agents such as drugs and environmental agents is being investigated. The benzopyranone-ring system is a molecular scaffold of considerable interest, and this scaffold is found in flavonoid natural products that have weak aromatase inhibitory activity. Medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aro- matase inhibitors. Several compounds in the

Topics: Antineoplastic Agents, Phytogenic; Aromatase; Benzopyrans; Blotting, Western; Breast Neoplasms; Cell Survival; Combinatorial Chemistry Techniques; Estradiol; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Indicators and Reagents; Isoflavones; Neoplasms, Hormone-Dependent; Peptide Library; Phytoestrogens; Plant Preparations; Tumor Cells, Cultured

Aromatase plays an important role in breast cancer development through its role in the synthesis of estrogen. Aromatase expression in breast tissue can be regulated by several mechanisms. The major promoter usage for aromatase expression in breast tumors (i.e. cAMP-stimulated promoters I.3 and II) is different from that in normal breast tissue (i.e. glucocorticoid-stimulated promoter I.4). Recent characterization of transcription factors that interact with the two important regulatory elements near promoters I.3 and II, i.e. S1 and CREaro, helps us better understand the mechanism of the switch of promoter usage between normal breast tissue and cancer tissue. It is thought that in normal breast tissue, the function of promoters I.3 and II is suppressed through the binding of EAR-2, COUP-TFI, and EARgamma to S1, and through the binding of Snail/Slug proteins to their binding site that quenchs the CREaro activity. In cancer tissue, the expression levels of EAR-2, COUP-TFI, EARgamma, Snail, and Slug decrease, and aromatase expression is then up regulated through the binding of ERRalpha-1 to S1 and the binding of CREB or related factors to CREaro. Results from this and other laboratories reveal that aromatase activity in aromatase expressing cells can also be modified by treatment with aromatase inhibitors and the antiestrogen ICI 182, 780. While aromatase inhibitors are used to treat breast cancer, the treatment has been found to increase the level of aromatase in the breast tissue of some patients. The enhancement of aromatase activity by aromatase inhibitors is thought to be due to a decrease of aromatase protein degradation by enzyme-inhibitor complex formation, up-regulation of the aromatase gene transcription through a cAMP-mediated mechanism, and an induction of aromatase expression by gonadtropins that are released from the pituitary in response to a reduction of estrogen levels in circulation in premenopausal women. Antiestrogen ICI 182, 780 has been found to suppress aromatase expression, but the mechanism has not yet been determined. In addition, aromatase activity and expression can be affected by environmental chemicals. A detailed structure-function study has revealed that flavones, but not isoflavones, are inhibitors of aromatase. It was found that flavones bind to the active site of aromatase in an orientation in which their rings-A and -C mimic rings-D and -C of the androgen substrate. The modulation of aromatase expression by endocrine disrup

Topics: Aromatase; Aromatase Inhibitors; Base Sequence; Binding Sites; Breast; Breast Neoplasms; Cyclic AMP Response Element-Binding Protein; DNA; Environmental Pollutants; Enzyme Inhibitors; Estrogen Receptor Modulators; Estrogens, Non-Steroidal; Female; Gene Expression Regulation, Enzymologic; Humans; Isoflavones; Molecular Sequence Data; Phytoestrogens; Plant Preparations; Promoter Regions, Genetic; Transcription Factors; Transcription, Genetic

Anthocyanins, which are natural plant pigments from the flavonoid family, represent substantial constituents of the human diet. Because some other bioflavonoids are known to have estrogenic activity, the aim of this study was to determine the estrogenic activity of the anthocyanine aglycones. Binding affinity to the estrogen receptor-alpha was 10,000- to 20,000-fold lower than that of the endogenous estrogen estradiol. In the estrogen receptor-positive cell line MCF-7, the anthocyanidins induced expression of a reporter gene. The tested anthocyanidins showed estrogen-inducible cell proliferation in two cell lines (MCF-7 and BG-1), but not in the receptor-negative human breast cancer cell line MDA-MB-231. The phytoestrogen-induced cell proliferation could be blocked by addition of the receptor antagonist 4-hydroxytamoxifen. Combination treatments with the endogenous estrogen estradiol resulted in a reduction of estradiol-induced cell proliferation. Overall, the tested anthocyanidins exert estrogenic activity, which might play a role in altering the development of hormone-dependent adverse effects.

Topics: Anthocyanins; Breast Neoplasms; Cell Division; Estradiol; Estrogen Receptor alpha; Estrogens; Estrogens, Non-Steroidal; Female; Gene Expression; Humans; Isoflavones; Ovarian Neoplasms; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Tamoxifen; Transcription, Genetic; Tumor Cells, Cultured

Environmental exposures, timing and duration of exposure, and one's genetic susceptibility all contribute to breast carcinoma and its progression. The purpose of this article was to identify known and suspected environmental causes of breast carcinoma, identify some environmental risk factors that may represent significant risk factors for certain groups, and describe current studies, supported by the National Institutes of Health/National Institute of Environmental Health Sciences, that clarify how environmental factors contribute to the development of breast carcinoma. Known and suspected environmental risk factors include organochlorine pesticides and other synthetic chemicals, hormonal factors (including exogenous endocrine disrupters), diet, tobacco and alcohol use, radiation, and magnetic fields. In at least 50% of breast carcinoma cases, none of the known risk factors apply. It is likely that an environmental component accounts for much of the unknown 50% of risk. Knowing the environmental factors for breast carcinoma development is an area that should be investigated intensely because it offers our best hope for prevention. Understanding why African-American women have a more aggressive form of breast carcinoma, whether they receive adequate follow-up treatment, and how these factors contribute to increased mortality rates requires further exploration. Data that demonstrate the lower incidence rate of breast carcinoma in Asian women, the relation to low fat diets and diets high in phytoestrogens, and how this might serve as a model for all women should be investigated. Finally, differences in behavioral and cultural attitudes, ethnicity, economic status, and life-style influences among different groups of women require further study to determine how these factors contribute to enhancing or reducing breast carcinoma risk.

Topics: Alcohol Drinking; Attitude to Health; Breast Neoplasms; Carcinogens; Carcinoma; Culture; Diet; Diet, Fat-Restricted; Environmental Exposure; Estrogens, Non-Steroidal; Ethnicity; Female; Follow-Up Studies; Health Behavior; Hormones; Humans; Isoflavones; Life Style; Magnetics; Neoplasms, Radiation-Induced; Pesticides; Phytoestrogens; Plant Preparations; Plants; Racial Groups; Research; Risk Factors; Smoking; Social Class; Survival Rate

The author is a former state legislator and feminist activist. Having traveled extensively in Asia, she questions the comparison of U.S. statistics regarding dietary/nutritional risk factors with those from countries whose public health standards are below that of the U.S. The author also notes that only recently has the U.S. had a critical mass of women in Congress that led to the funding of the first Women's Health Initiative. Countries in Asia have few women in positions of political power to advocate for public policies regarding women's health issues, especially concerning the gathering of data regarding breast carcinoma, which is considered a culturally sensitive topic. Although soy is considered a healthy staple of the majority of Asian diets because of its phytoestrogens, there is a mixed message to American consumers because cancer, rather than heart disease, is the leading cause of death among Asian females.

Topics: Asia; Breast Neoplasms; Carcinoma; Consumer Advocacy; Culture; Diet; Estrogens, Non-Steroidal; Ethnicity; Female; Health Promotion; Humans; Isoflavones; Nutritional Physiological Phenomena; Phytoestrogens; Plant Preparations; Plants; Public Policy; Racial Groups; Risk Factors; United States; Women's Health

Topics: Breast Neoplasms; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Family Practice; Female; Humans; Isoflavones; Menopause; Phytoestrogens; Plant Preparations; United States

Isoflavones and others phytoestrogens have been suggested to be anticarcinogenic. Anti-aromatase, antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. In this study, we explored some mechanisms by which they can exert cancer-preventive effects. Phytoestrogens were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. We found that isoflavonoids and compounds which presented the phenolic B ring in the 3 position on the pyran ring preferentially inhibited 3beta-HSD and/or 17beta-HSD activities than aromatase activity. We also evaluated their interactions with the estrogen receptor using a stably transfected human breast cancer cell line (MVLN). On the other hand phytoestrogens were evaluated for their effects on the proliferation in estrogen-dependent (MCF-7) and independent (MDA-MB231) human breast cancer cells. We established a relationship structure-activity and determined regions or/and substituents essential for these different activities. However, at high concentrations it seems that some phytoestrogens exert their protection against breast cancer through other estrogen-independent mechanisms.

Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxysteroid Dehydrogenases; Anti-Inflammatory Agents, Non-Steroidal; Aromatase Inhibitors; Benzopyrans; Breast Neoplasms; Cell Division; Cells, Cultured; Enzyme Inhibitors; Estrogen Antagonists; Estrogens, Non-Steroidal; Fabaceae; Humans; Isoflavones; Luciferases; Magnetic Resonance Spectroscopy; Microsomes; Phytoestrogens; Placenta; Plant Preparations; Plants, Medicinal; Pterocarpans; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Breast Neoplasms; Estrogens, Non-Steroidal; Genistein; Hot Flashes; Humans; Isoflavones; Phytoestrogens; Plant Preparations

Cruciferous vegetable extracts from freeze-dried cabbage (FDC), freeze-dried fermented cabbage (FDS), and acidified Brussels sprouts (ABS) were prepared by exhaustive extraction with ethyl acetate. Estrogenic and antiestrogenic effects of these extracts were analyzed. To identify whether the extracts are potential estrogen receptor (ER) ligands that can act as agonists or antagonists, the binding affinity of extracts for the ER was measured using a competitive radiometric binding assay. The extracts bound with low affinity to the ER, and the relative binding affinity is estradiol > FDS > FDC > ABS. These extracts were evaluated for their estrogenic and antiestrogenic activities in estrogen-dependent human breast cancer (MCF-7) cells using as endpoints proliferation and induction of estrogen-responsive pS2 gene expression, which was analyzed using Northern blot assay. At low concentrations (5-25 ng/mL) all of the extracts reduced 1 nM estradiol-induced MCF-7 cell proliferation. Extracts at 25 ng/mL also inhibited estradiol-induced pS2 mRNA expression. At higher extract concentrations (50 ng/mL-25 microg/mL), however, increased proliferation in MCF-7 cells was observed. Similarly, expression of the pS2 gene was induced by higher extract concentrations (0.25-25 microg/mL). The pure estrogen antagonist, ICI 182,780, suppressed the cell proliferation induced by the extracts as well as by estradiol and also the induction of pS2 expression by the extracts. The ER subtype-selective activities of FDC and FDS were analyzed using a transfection assay in human endometrial adenocarcinoma (HEC-1) cells. FDS acted as an ERalpha-selective agonist while FDC fully activated both ER-alpha and ER-beta. Growth of the ER-negative MDA-231 cells was not affected by the extracts or by estradiol. This study demonstrates that cruciferous vegetable extracts act bifunctionally, like an antiestrogen at low concentrations and an estrogen agonist at high concentrations.

Topics: Breast Neoplasms; Cell Division; Estrogens; Estrogens, Non-Steroidal; Fermentation; Humans; Isoflavones; Phytoestrogens; Plant Extracts; Plant Preparations; Tumor Cells, Cultured; Vegetables

We analyzed the intake of selected foods that contain phytoestrogens in relation to breast cancer (BC) risk using data from a hospital-based case-control study performed in Mexico City from 1994 to 1995. A total of 198 women with BC, aged 21-79 years, were individually age matched to an identical number of women with no breast disease. By a direct interview, information on socioeconomic characteristics and diet was obtained. A semiquantitative questionnaire was used to estimate the frequency of consumption of 95 foods. The effect of selected foods that contain phytoestrogens on BC risk was estimated using logistic regression models. The adjusted odds ratio for the consumption of more than one slice of onion per day and BC was 0.27 (95% confidence interval = 0.16-0.47), with a statistically significant trend (p < 0.001). This protective effect remained after adjustment for known risk factors of BC. Among premenopausal women, there was also a protective and significant effect due to the intake of lettuce and spinach and nonsignificant protective effects for the consumption of apples and herbal tea. Additional studies aimed at evaluating the potential protective effect of particular phytoestrogens on BC risk are needed.

Topics: Adult; Aged; Anticarcinogenic Agents; Breast Neoplasms; Case-Control Studies; Diet; Diet Records; Estrogens, Non-Steroidal; Female; Food Analysis; Humans; Interviews as Topic; Isoflavones; Logistic Models; Mexico; Middle Aged; Phytoestrogens; Plant Preparations; Plants, Edible; Risk Factors; Socioeconomic Factors; Surveys and Questionnaires

Members of the flavonoid class of phytochemicals have previously been demonstrated to possess estrogenic activity in a number of hormonally responsive systems. We have performed the present study to characterize the estrogenic and antiestrogenic activity of flavonoids in the estrogen receptor (ER)-positive MCF-7 human breast cancer cell line. Using an ER-dependent reporter gene assay and an ER competition binding assay, we have identified phytochemicals possessing estrogenic and antiestrogenic activities, which appeared to correlate directly with their capacity to displace [3H]estradiol from ER. Several flavonoids, including kaempferide, apigenin, and flavone, were distinct, in that their antiestrogenic activity did not appear to correlate with binding to ER, and therefore their suppression of estrogen-mediated gene transactivation and proliferation may occur independent of direct antagonism of the receptor. Further examination in HEK-293 cells transfected with ERalpha or ERbeta demonstrated potent antagonism with kaempferide and apigenin, while flavone was weakly antagonistic only toward ERP. These results suggest that the receptor binding-independent antiestrogenic chemicals may function through alternate signaling pathways as indirect ER modulators in a receptor- and cell type-specific manner. We conclude that antiestrogenic activities of flavonoid phytochemicals may occur through ER binding-dependent and -independent mechanisms and that the binding-independent antiestrogen activity of certain flavonoids is biologically significant in regulation of breast cancer cell proliferation.

Topics: Binding, Competitive; Breast Neoplasms; Cell Division; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Flavonoids; Humans; Isoflavones; Luciferases; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Tumor Cells, Cultured

Topics: Breast Neoplasms; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Progestins; Risk Factors

It is well known that plants contain substances with oestrogen activity comparable to that in animals. In animals, oestrogens are steroid hormones while plants contain oestrogen with various chemical characteristics, referred to as phytoestrogens. These especially, may be responsible for part of the effects of Chinese herbal prescriptions for postmenopausal disorders in which oestrogen deficiency is considered the primary cause. In addition, the presence or absence of oestrogen activity in herbal medicine is considered extremely important for patients in whom oestrogen administration is contraindicated. The most important action of oestrogen is the transcriptional regulation of specific genes via oestrogen receptors (ER). Therefore, we have established a highly sensitive bioassay system by placing oestrogen responsive elements (ERE) upstream to the reporter gene, and have used this assay to determine the oestrogen activity in herbal medicine. As a result, phytoestrogens were found in many Chinese herbal prescriptions for postmenopausal disorder, and some prescriptions were considered to effectively administer hormone replacement therapy (HRT). However, since oestrogen activities in most Chinese herbal prescriptions were thought to be weak, it was considered that these prescriptions improved postmenopausal disorder based on a mechanism differing from that of oestrogen replacement therapy.

Topics: Biological Assay; Breast Neoplasms; Estrogens, Non-Steroidal; Female; Gene Expression Regulation, Enzymologic; Humans; Isoflavones; Luciferases; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Preparations; Postmenopause; Recombinant Proteins; Sensitivity and Specificity; Transfection; Tumor Cells, Cultured

Resveratrol, a natural phytoestrogen, has been reported to promote differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation of prostate cancer cell lines. In the present study we tested the effects of resveratrol on the increased proliferation of human AHTO-7 osteoblastic cell line induced by conditioned media (CM) from a panel of carcinoma cell lines. This compound was found to modulate AHTO-7 proliferation in a tamoxifen-sensitive mechanism at lower concentrations, but failed to induce the osteoblast differentiation marker alkaline phosphatase (ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition) upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM) cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced. Direct addition of resveratrol affected only supernatants of cell lines (<25% inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts. Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations exceeding 5 microM, altered cell cycle distribution of all prostate cancer cell lines in concentrations as low as 0.5 microM, but did not inhibit the production of osteoblastic factors by these lines. In conclusion, resveratrol failed to induce ALP activity as marker of osteoblast differentiation in human osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic carcinoma-derived growth factors in concentrations significantly lower than those to reduce growth of cancer cells, thus effectively modulating tumor - osteoblast interaction.

Topics: Alkaline Phosphatase; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Carcinoma, Renal Cell; Cell Differentiation; Cell Line; Culture Media, Conditioned; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Kidney Neoplasms; Lung; Male; Osteoblasts; Pancreatic Neoplasms; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Resveratrol; Stilbenes; Tamoxifen; Tumor Cells, Cultured

Transforming growth factor-alpha (TGF-alpha) contributes to the progression of mammary carcinogenesis in part through synergistic augmentation of estradiol (E2) action. To investigate this further, we sought to determine (1) whether the duration of TGF-alpha treatment might influence the nature of the TGF-alpha/E2 interaction, and (2) whether TGF-alpha would behave in a similar manner when combined with phytoestrogens. To this end, we transfected T47-D breast cancer cells with an estrogen-responsive reporter and then treated the cells (for 4-48 h) with varying concentrations of TGF-alpha, E2, the antiestrogen 4-hydroxy-tamoxifen (HOT), and/or one of three phytoestrogens. Our findings revealed that TGF-alpha has short-term synergistic and long-term inhibitory effects on E2- and phytoestrogen-regulated gene expression. Furthermore, this secondary inhibition of E2 action by TGF-alpha was similar in magnitude to that imposed by HOT. These findings demonstrate a novel role for TGF-alpha and invite reevaluation of current models regarding TGF-alphas interactions with E2 in breast cancer cells. Our results also raise the possibility that phytoestrogens, which interact with TGF-alpha in a manner conceptually identical to that of E2, may subserve a regulatory function in breast cancer cells.

Topics: Adenocarcinoma; Breast Neoplasms; Drug Synergism; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Gene Expression Regulation, Neoplastic; Humans; Isoflavones; Luciferases; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Tamoxifen; Transfection; Transforming Growth Factor alpha; Tumor Cells, Cultured

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Animals; Breast Neoplasms; Colonic Neoplasms; Environmental Exposure; Estrogen Receptor beta; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Signal Transduction; Transcription Factors

Topics: Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Topics: Breast Neoplasms; Dietary Fats, Unsaturated; Estrogens, Non-Steroidal; Fatty Acids, Unsaturated; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations

Topics: Adenocarcinoma; BRCA1 Protein; Breast; Breast Neoplasms; Cells, Cultured; Epithelial Cells; Estrogens; Estrogens, Non-Steroidal; Female; Gene Expression Regulation; Genes, BRCA1; Genistein; Humans; Isoflavones; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Signal Transduction; Tumor Cells, Cultured

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Breast Neoplasms; Estrogens, Non-Steroidal; Female; France; Humans; Isoflavones; Mammary Neoplasms, Experimental; Mice; Phytoestrogens; Plant Preparations; Plants; Platelet Aggregation Inhibitors; Resveratrol; Stilbenes; Wine

Phytoestrogens can exhibit agonistic actions on estrogen-dependent gene expression in breast cancer cells. Since several different phytoestrogens may be found within a single dietary plant source, we sought to investigate whether estrogen-dependent gene expression may be further influenced by the collective treatment of breast cancer cells with multiple phytoestrogens. Accordingly, we transfected MCF-7 breast cancer cells with estrogen-responsive reporters followed by treatment with one of four phytoestrogens (genistein, daidzein, formononetin, and equol) or a combination of these in the absence of estradiol. Our results demonstrated clear-cut agonistic effects of phytoestrogens on estrogen-dependent gene expression. Moreover, combinatorial treatment consistently stimulated reporter activity above that observed for individual phytoestrogens. Inasmuch as the phytoestrogens tested are frequently found together in food sources, these combinatorial responses may more accurately reflect the consequences of in vivo exposure.

Topics: Breast Neoplasms; Chromans; Drug Interactions; Equol; Estrogens; Estrogens, Non-Steroidal; Gene Expression; Genistein; Humans; Isoflavones; Luciferases; Phytoestrogens; Plant Preparations; Transfection; Tumor Cells, Cultured

Topics: Animals; Breast Neoplasms; Cardiovascular Diseases; Estrogen Replacement Therapy; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Male; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Plants; Prostatic Neoplasms

Bioassay-guided fractionation of a methanolic extract of a Thai crude drug, derived from heartwood of Anaxagorea luzonensis A. Gray (Annonaceae), resulted in the isolation of 8-isopentenylnaringenin (1) as an estrogen agonist with a activity of about an order of magnitude greater than genistein. Various flavonoids possessing isopentenyl side chains in the A-ring have been prepared and evaluated for their ability to bind estrogen receptor. In addition, enantiomers of 1 were separated and the respective enantiomers were assayed. These studies have demonstrated that the presence of an 8-isopentenyl group is an important factor for binding. Flavones, flavanones and flavonols having an isopentenyl substituent at C-8 exhibited an appreciable affinity for estrogen receptor. Conversely, isoflavones possessing an 8-isopentenyl substituent at C-8 did not show this activity. Movement of the isopentenyl group from position 8 to 6 resulted in loss of the activity. No significant difference was observed between 2(S)- and 2(R)-enantiomers of 1 in their binding affinity. Prenylflavonoids are reported to possess a wide range of biological activities; however, estrogenic activity has not been described.

Topics: Breast Neoplasms; Cell Division; Estradiol; Estrogens, Non-Steroidal; Female; Genistein; Humans; Isoflavones; Medicine, East Asian Traditional; Molecular Structure; Phytoestrogens; Plant Extracts; Plant Preparations; Plants, Medicinal; Receptors, Estradiol; Stereoisomerism; Structure-Activity Relationship; Thailand; Tumor Cells, Cultured

Phytoestrogen effects on estrogen action and tyrosine kinase activity have been proposed to contribute to cancer prevention. To study these mechanisms, a number of phytoestrogens and related compounds were evaluated for their effects on DNA synthesis (estimated by thymidine incorporation analysis) in estrogen-dependent MCF-7 cells in the presence of estradiol (E2), tamoxifen, insulin, or epidermal growth factor. We observed that 1) at 0.01-10 microM, genistein and coumestrol enhanced E2-induced DNA synthesis, as did 10 microM enterolactone. Chrysin at 1.0-10 microM and 10 microM luteolin or apigenin inhibited E2-induced DNA synthesis, as did all compounds at > 10 microM, 2) tamoxifen enhanced genistein-induced DNA synthesis but inhibited DNA synthesis induced by all other compounds, and 3) genistein enhanced insulin- and epidermal growth factor-induced DNA synthesis at 0.1-1.0 and 0.1-10 microM, respectively. At higher concentrations, inhibition was observed. Similar effects were seen with coumestrol. In conclusion, the effects of phytoestrogens in the presence of E2 or growth factors are concentration dependent and variable. At low concentrations, genistein and coumestrol significantly enhanced E2-induced and tyrosine kinase-mediated DNA synthesis; at high concentrations, inhibition was observed. Differing effects were observed with the other compounds. The variable effects of phytoestrogens on DNA synthesis must be considered when their roles in cancer prevention or treatment are evaluated.

Topics: 4-Butyrolactone; Anticarcinogenic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Chamomile; Coumestrol; DNA, Neoplasm; Epidermal Growth Factor; Estradiol; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Humans; Insulin; Isoflavones; Lignans; Luteolin; Oils, Volatile; Phytoestrogens; Plant Preparations; Plants, Medicinal; Tamoxifen; Tumor Cells, Cultured

Topics: Animals; Breast Neoplasms; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Postmenopause; Rats; Risk Factors; Treatment Outcome

Experimental and epidemiologic studies support the view that soyfoods prevent cancer as well as diseases and symptoms associated with estrogen deficiency. Recent research suggests that the isoflavonoid genistein, a phytoestrogen found in abundance in soyfoods, may be one of the principal molecular components responsible for these health benefits. In this study we investigated the effects of a broad physiologically relevant concentration range of genistein on estrogen receptor (ER) binding, induction of the estrogen-regulated antigen pS2, and cell proliferation rate in ER(+) and ER(-) human breast cancer cells grown in vitro. Dose response to genistein was compared with that of estradiol, tamoxifen, and several other structurally similar iso- and bioflavonoids (e.g., equol, kaempferol, and quercetin). Our results revealed that genistein has potent estrogen agonist and cell growth-inhibitory actions over a physiologically achievable concentration range (10 nM-20 microM). Other flavonoids over the same concentration range were good estrogen agonists and poor cell growth inhibitors (equol) or poor estrogen agonists and potent growth inhibitors (kaempferol and quercetin). The growth-inhibitory actions of flavonoids were distinctly different from those of triphenyl antiestrogens like tamoxifen. In summary, our results reveal that genistein is unique among the flavonoids tested, in that it has potent estrogen agonist and cell growth-inhibitory actions over a physiologically relevant concentration range.

Topics: Anticarcinogenic Agents; Breast; Breast Neoplasms; Cell Division; Chromans; DNA, Neoplasm; Dose-Response Relationship, Drug; Epithelial Cells; Epithelium; Equol; Estradiol; Estrogen Antagonists; Estrogens, Non-Steroidal; Female; Flavonoids; Genistein; Humans; Isoflavones; Kaempferols; Phytoestrogens; Plant Preparations; Protein Binding; Quercetin; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured

We investigated the estrogenic activity of various environmental pollutants (xenobiotics), in particular the xenoestrogen o,p-DDT, and compared their effects with those of endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding capacity, induction of estrogen end products, and activation of cell proliferation in estrogen-sensitive human breast cancer cells in monolayer culture. We also quantified the levels of phytoestrogens in extracts of some common foods, herbs, and spices and in human saliva following consumption of a high phytoestrogen food source (soy milk) to compare phytoestrogen abundance and bioavailability relative to the reported xenoestrogen burden in humans. Results show that natural endogenous estrogens, phytoestrogens, mycoestrogens, and xenoestrogens bind estrogen receptor (ER) in intact cells, but demonstrate marked differences in their ability to induce end products of estrogen action and to regulate cell proliferation. All of the different classes of estrogens stimulated cell proliferation at concentrations that half-saturated ER, but only some classes were able to induce estrogen-regulated end products. Genistein, a common phytoestrogen found in soy foods, differed from the xenoestrogen DDT in its effects on cell proliferation and ability to induce estrogen-regulated end products. Moreover, we found that many of the foods, herbs, and spices commonly consumed by humans contain significant amounts of phytoestrogens, and consumption of soy milk, a phytoestrogen-rich food, markedly increases the levels of phytoestrogens in saliva. In conclusion, our in vitro results predict that a diet high in phytoestrogens would significantly reduce the binding of weak xenoestrogens to ER in target tissues in vivo.

Topics: Breast Neoplasms; Cell Division; DDT; Diet; Environmental Health; Environmental Pollutants; Estradiol Congeners; Estrogens; Estrogens, Non-Steroidal; Female; Food Analysis; Humans; Isoflavones; Neoplasms, Hormone-Dependent; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Saliva; Tumor Cells, Cultured

Topics: Breast Neoplasms; Case-Control Studies; Diet; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Lignans; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Phyto-oestrogens are a group of naturally occurring chemicals derived from plants; they have a structure similar to oestrogen, and form part of our diet. They also have potentially anticarcinogenic biological activity. We did a case-control study to assess the association between phyto-oestrogen intake (as measured by urinary excretion) and the risk of breast cancer.. Women with newly diagnosed early breast cancer were interviewed by means of questionnaires, and a 72 h urine collection and blood sample were taken before any treatment started. Controls were randomly selected from the electoral roll after matching for age and area of residence. 144 pairs were included for analysis. The urine samples were assayed for the isoflavonic phyto-oestrogens daidzein, genistein, and equol, and the lignans enterodiol, enterolactone, and matairesinol.. After adjustment for age at menarche, parity, alcohol intake, and total fat intake, high excretion of both equol and enterolactone was associated with a substantial reduction in breast-cancer risk, with significant trends through the quartiles: equol odds ratios were 1.00, 0.45 (95% CI 0.20, 1.02), 0.52 (0.23, 1.17), and 0.27 (0.10, 0.69)--trend p = 0.009--and enterolactone odds ratios were 1.00, 0.91 (0.41, 1.98), 0.65 (0.29, 1.44), 0.36 (0.15, 0.86)--trend p = 0.013. For most other phytoestrogens there was a reduction in risk, but it did not reach significance. Difficulties with the genistein assay precluded analysis of that substance.. There is a substantial reduction in breast-cancer risk among women with a high intake (as measured by excretion) of phyto-oestrogens-particularly the isoflavonic phyto-oestrogen equol and the lignan enterolactone. These findings could be important in the prevention of breast cancer.

Topics: 4-Butyrolactone; Breast Neoplasms; Case-Control Studies; Chromans; Diet; Equol; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Lignans; Middle Aged; Phytoestrogens; Plant Preparations; Plants; Risk Factors

Thirteen isoflavonoids, flavonoids, and lignans, including some known phytoestrogens, were evaluated for their effects on DNA synthesis in estrogen-dependent (MCF-7) and -independent (MDA-MB-231) human breast cancer cells. Treatment for 24 hours with most of the compounds at 20-80 microM sharply inhibited DNA synthesis in MDA-MB-231 cells. In MCF-7 cells, on the other hand, biphasic effects were seen. At 0.1-10 microM, coumestrol, genistein, biochanin A, apigenin, luteolin, kaempferol, and enterolactone induced DNA synthesis 150-235% and, at 20-90 microM, inhibited DNA synthesis by 50%. Treatment of MCF-7 cells for 10 days with genistein or coumestrol showed continuous stimulation of DNA synthesis at low concentrations. Time-course experiments with genistein in MCF-7 cells showed effects to be reversed by 48-hour withdrawal of genistein at most concentrations. Induction of DNA synthesis in MCF-7 cells, but not in MDA-MB-231 cells, is consistent with an estrogenic effect of these compounds. Inhibition of estrogen-dependent and -independent breast cancer cells at high concentrations suggests additional mechanisms independent of the estrogen receptor. The current focus on the role of phytoestrogens in cancer prevention must take into account the biphasic effects observed in this study, showing inhibition of DNA synthesis at high concentrations but induction at concentrations close to probable levels in humans.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Coumestrol; DNA; Estradiol; Estrogens, Non-Steroidal; Flavonoids; Genistein; Humans; Isoflavones; Kinetics; Lignans; Phytoestrogens; Plant Preparations; Tumor Cells, Cultured

The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects. Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (approximately 3-10 microM) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells. This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol. Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems. The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine.

Topics: Breast Neoplasms; Cardiovascular Diseases; Cell Division; Estradiol; Estrogens, Non-Steroidal; Female; Genes, Reporter; Humans; Isoflavones; Organ Specificity; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Resveratrol; Rosales; Stilbenes; Transcriptional Activation; Tumor Cells, Cultured; Wine

In spite of many known and suspected factors associated with the risk of breast cancer there has until recently been no explanation for its continuing increase in women of Western societies over recent decades or why there has not been an equivalent increase in women of most Asian and other less Westernized societies. It has long been suspected that a significant factor has been an increasing change of diet in Western societies from one predominantly vegetarian to one with a high content of meat and dairy products as well as 'refined' foods. Although diet has long been suspected there has otherwise been no real explanation as to the mechanism of the change in incidence of breast cancer.. A comprehensive literature review has been made of aetiological factors and associations concerning breast cancer to determine whether any consistent trend can explain the rising incidence in Western societies.. There are a number of likely contributory factors but there is now accumulating evidence that the single most important difference is that people having a vegetarian diet have a high intake of legumes and other plant foods containing a variety of lignans and isoflavonoids. These appear to have an important role as nature's sex hormone modulators. These agents appear to be biologically active in a number of ways not yet completely understood but they do have both a weak oestrogenic effect and an anti-oestrogenic competitive effect, thus reducing the potential carcinogenic action of prolonged oestrogen activity. A probable additional benefit of such diets could be the role of dietary fibre.. A major problem of Western diets may not be the presence of meat or dairy products in the diet but the absence of desirable ingredients of vegetarian diets, namely dietary fibre and certain plant lignans and isoflavonoids. A modification of diet to include a greater proportion of fibre and soy or other leguminous plant food should be studied. Alternatively addition of more fibre and lignans and especially isoflavonoids to traditional Western diets would seem worthy of serious investigation. Such influences appear to have their greatest impact early in life and therefore could be especially important for girls and young women in Western societies.

Topics: Breast Neoplasms; Dietary Fiber; Estrogens, Non-Steroidal; Fabaceae; Female; Humans; Incidence; Isoflavones; Lignans; Phytoestrogens; Phytotherapy; Plant Preparations; Plants; Plants, Medicinal; Risk Factors; Western World

Several plant estrogens, especially coumestrol and genistein, were found to reduce the conversion of [3H]estrone to [3H] 17 beta-estradiol catalyzed by estrogen-specific 17 beta-hydroxysteroid oxidoreductase Type 1 (E.C. 1.1.1.62) in vitro. Coumestrol, the most potent inhibitor in our experiments, is the best inhibitor of the enzyme known to date. All compounds with inhibitory effects were also estrogenic. However, structural demands for 17 beta-HSOR Type 1 inhibition and estrogenicity of tested compounds in breast cancer cells (judged by increased cell proliferation) were not identical. Zearalenone and diethylstilbestrol, both potent estrogens, did not inhibit 17 beta-HSOR Type 1. Thus, changes in the estrogen molecule may discriminate between active sites of 17 beta-HSOR Type 1 and estrogen binding sites of the ER. The effects of these compounds in vivo cannot be predicted on the basis of these results. Inhibition of 17 beta-HSOR Type 1 enzyme could lead to a decrease in the availability of the highly active endogenous estrogen. However, these compounds are estrogenic per se, and they may thus replace endogenous estrogens. Additional studies are needed to further understand the role of these plant estrogens in the etiology of hormone-dependent cancers. It is not easily conceivable how the chemopreventive action of Asian diets, possibly mediated by phytoestrogens in soya products, can be based on the inhibition of estrone reduction at the target cells by phytoestrogens or related compounds, unless they are "incomplete estrogens" (i.e., unable to induce all effects typical of endogenous estrogens).

Topics: 17-Hydroxysteroid Dehydrogenases; Breast Neoplasms; Cell Division; Coumarins; Estradiol; Estrogens, Non-Steroidal; Estrone; Flavonoids; Glycyrrhetinic Acid; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Sitosterols; Tumor Cells, Cultured