phytoestrogens and Cell-Transformation--Neoplastic

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

Ulcerative colitis (UC) is a condition at increased risk for colorectal carcinoma (CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors (extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogen receptors (ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anti-carcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.

Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Cell Transformation, Neoplastic; Colitis, Ulcerative; Colorectal Neoplasms; Estrogen Receptor beta; Humans; Phytoestrogens; Protective Factors; Receptors, Estrogen; Risk Factors; Signal Transduction

Genetically modified food (GMF) creates evident threat to consumers' health. In spite of assurances of biotechnologists, DNA of transgenic plants is instable, so, synthesis of foreign, allergenic proteins is possible. Due to high trypsin inhibitor content the GMF is digested much more slowly what, alike Bt toxin presence, increases probability of alimentary canal diseases. Next threats are bound to the presence of fitoestrogens and residues of Roundup pesticide, that can diminish reproductiveness; and even lead to cancerogenic transformation through disturbance of human hormonal metabolism. In spite of food producers and distributors assurances that food made of GMF raw materials is marked, de facto consumers have no choice. Moreover, along the food law products containing less than 0.9% of GMF protein are not included into genetically modified food.

Topics: Cell Transformation, Neoplastic; Digestive System Diseases; DNA Sequence, Unstable; Food Analysis; Food, Genetically Modified; Foodborne Diseases; Humans; Phytoestrogens; Plants, Genetically Modified

Genistein is of great interest for its implications as an anticancer compound. We compared the effects of daily subcutaneous injections of 1mg/kg BW of genistein and vehicle (2% DMSO in peanut oil) for 20 weeks on N-nitroso-N-methylurea (NMU)-induced tumorigenesis in adult female rats. Genistein significantly increased tumor cross-sectional area and tumor multiplicity but not the tumor incidence and latency period when compared with the vehicle treated group. The serum E(2) levels of genistein treated group were significantly higher than those of the vehicle treated group at 1 and 2 months after treatment which is the time when most of the rats developed tumors. There were no significant differences in the length of the estrous cycle, food consumption and weights of body, livers, uteri and ovaries between the two groups. Our data shows that supplementation of genistein at a dosage comparable to the isoflavone consumption in humans did not affect the reproductive system but resulted in enhancement of NMU-induced tumorigenesis in adult female rats. Thus, the supplementation of soy isoflavone in premenopausal women may potentially potentiate the risk of breast cancer.

Topics: Animals; Antineoplastic Agents; Body Weight; Carcinogens; Cell Transformation, Neoplastic; Estradiol; Estrous Cycle; Female; Genistein; Mammary Neoplasms, Animal; Methylnitrosourea; Organ Size; Phytoestrogens; Rats; Rats, Sprague-Dawley

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

For the simultaneous assessment of in vitro carcinogenicity and mutagenicity of phytoestrogens, the abilities of 5 phytoestrogens, daidzein, genistein, biochanin A, prunetin, and coumestrol, to induce cell transformation and genetic effects were examined using the Syrian hamster embryo (SHE) cell model. Cellular growth was inhibited by all phytoestrogens in a concentration-related manner. The growth inhibitory effect of the compounds was ranked: genistein, prunetin > coumestrol > biochanin A > daidzein, which did not correspond to their apoptosis-inducing abilities. Morphological transformation in SHE cells was elicited by all phytoestrogens, except, prunetin. The transforming activities were ranked as follows: genistein > coumestrol > daidzein > biochanin A. Somatic mutations in SHE cells at the Na(+)/K(+) ATPase and hprt loci were induced only by genistein, coumestrol, or daidzein. Chromosome aberrations were induced by genistein or coumestrol, and aneuploidy in the near diploid range was occurred by genistein or biochanin A. Genistein, biochanin A or daidzein induced DNA adduct formation in SHE cells with the abilities: genistein > biochanin A > daidzein. Prunetin was negative for any of these genetic endpoints. Our results provide evidence that genistein, coumestrol, daidzein and biochanin A induce cell transformation in SHE cells and that the transforming activities of these phytoestrogens correspond to at least 2 of the mutagenic effects by each phytoestrogen, i.e., gene mutations, chromosome aberrations, aneuploidy or DNA adduct formation, suggesting the possible involvement of mutagenicity in the initiation of phytoestrogen-induced carcinogenesis.

Topics: Animals; Anticarcinogenic Agents; Apoptosis; Cell Line; Cell Transformation, Neoplastic; Chromosome Aberrations; Coumestrol; Cricetinae; DNA Adducts; Dose-Response Relationship, Drug; Embryo, Mammalian; Estrogens, Non-Steroidal; Genistein; Isoflavones; Mesocricetus; Metaphase; Models, Chemical; Mutagens; Mutation; Phytoestrogens; Plant Preparations; Time Factors

Using purified human type 1 estrogen sulfotransferase (hEST1), we show that the best substrate for this enzyme is 2-hydroxy-catecholestrogen. The enzyme also catalyzes the transformation of 4-hydroxy-estrogens and 16-hydroxy-estrogens, but with a lower affinity. We also present evidence to indicate that estrogen sulfotransferase may play a role in processes other than the detoxification and elimination of steroids. Indeed, hEST1 may also be involved in the production of stable precursors for local steroid biosynthesis or in the activation of promutagenic estrogen metabolites into carcinogens.

Topics: Carcinogens; Cell Transformation, Neoplastic; Contraceptives, Oral; Estrogens; Estrogens, Catechol; Estrogens, Non-Steroidal; Fungal Proteins; Humans; Isoflavones; Phytoestrogens; Plant Preparations; Protective Agents; Saccharomyces cerevisiae Proteins; Telomerase

Prostate cancer is one of the most common male cancers in Western countries, yet the incidence of this fatal disease remains low in Asian populations. Environmental factors such as diet play an important role in hormone-dependent cancer etiology, and a high phytoestrogen intake may be one factor contributing to the low prostate cancer mortality in Eastern populations. In this study, we investigated the effects of the phytoestrogens genistein, daidzein, coumestrol, and equol on cell growth and DNA damage (strand breakage) in two human prostate tumor cell lines: androgen receptor-positive LNCaP and androgen receptor-negative PC-3. Each compound caused growth inhibition at physiologically relevant concentrations (<10 microM). Genistein induced DNA damage in both cell lines at <10 microM. Daidzein inhibited cell growth at 10-100 microM yet had no effect on DNA damage at up to 500 microM. Thus, despite their structural similarities, different phytoestrogens inhibit prostate tumor cell growth by independent mechanisms.

Topics: Antineoplastic Agents, Phytogenic; Cell Division; Cell Transformation, Neoplastic; Chromans; Coumestrol; DNA Damage; Equol; Estrogens, Non-Steroidal; Genistein; Humans; Isoflavones; Male; Phytoestrogens; Plant Preparations; Prostatic Neoplasms; Tumor Cells, Cultured

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