leptin and Breast-Neoplasms

leptin has been researched along with Breast-Neoplasms* in 360 studies

Reviews

63 review(s) available for leptin and Breast-Neoplasms

ArticleYear
Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.
    Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 2023, Volume: 25, Issue:3

    Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

    Topics: Breast Neoplasms; Female; Humans; Leptin; Obesity; Peroxisome Proliferator-Activated Receptors; PPAR alpha; Signal Transduction; Tumor Microenvironment

2023
Insight on the Role of Leptin: A Bridge from Obesity to Breast Cancer.
    Biomolecules, 2022, 09-29, Volume: 12, Issue:10

    Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

    Topics: Adipokines; Breast Neoplasms; Female; Humans; Leptin; Obesity; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt

2022
Pro-angiogenic activity and vasculogenic mimicry in the tumor microenvironment by leptin in cancer.
    Cytokine & growth factor reviews, 2021, Volume: 62

    The acquired ability to induce the formation of a functional vasculature is a hallmark of cancer. Blood vessels in tumors are formed through various mechanisms, among the most important in cancer biology, angiogenesis, and vasculogenic mimicry have been described. Leptin is one of the main adipokines secreted by adipocytes in normal breast tissue and the tumor microenvironment. Here, we provide information on the relationship between leptin and the development of angiogenesis and vasculogenic mimicry in different types of cancer. Here, we report that leptin activates different pathways such as JAK-STAT3, MAPK/ERK, PKC, JNK, p38, and PI3K-Akt to induce the expression of various angiogenic factors and vasculogenic mimicry. In vivo models, leptin induces blood vessel formation through the PI3K-Akt-mTOR pathway. Interestingly, the relationship between leptin and vasculogenic mimicry was more significant in breast cancer. The information obtained suggests that leptin could be playing an essential role in tumor survival and metastasis through the induction of vascular mechanisms such as angiogenesis and vasculogenic mimicry; thus, leptin-induced pathways could be suggested as a promising therapeutic target.

    Topics: Breast Neoplasms; Female; Humans; Leptin; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Tumor Microenvironment

2021
The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer.
    Frontiers in immunology, 2021, Volume: 12

    Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

    Topics: Adipose Tissue; Animals; Breast; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Female; Humans; Immunity, Cellular; Leptin; Lymphocytes, Tumor-Infiltrating; Mice, Transgenic; Receptors, Leptin; T-Lymphocytes, Cytotoxic; Tumor Microenvironment

2021
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors.
    Annales medico-psychologiques, 2021, Volume: 179, Issue:2

    The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

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2021
Effects of Diet and Exercise-Induced Weight Loss on Biomarkers of Inflammation in Breast Cancer Survivors: A Systematic Review and Meta-analysis.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021, Volume: 30, Issue:6

    Adiponectin, leptin, and pro- and anti-inflammatory cytokines are implicated in breast cancer risk and recurrence. Weight loss, via the dynamic interplay of energy balance through exercise and/or caloric restriction, decreases risk of breast cancer recurrence.. We investigated the effects of lifestyle modifications (exercise only, or combined caloric restriction and exercise) on adipokines, IL2, IL6, IL8, IL10, C-reactive protein (CRP), and TNFα biomarkers in breast cancer survivors. Searches were completed in June and July of 2019 to identify randomized controlled trials that met inclusion criteria. Weighted mean difference was calculated using random- or fixed-effects models based on the heterogeneity of the studies.. 2501 records were identified, with 30 ultimately meeting inclusion criteria of the systematic review; 21 studies provided data suitable for meta-analysis. We observed leptin levels were significantly reduced in the exercise-only group compared with sedentary control [WMD -5.66; 95% confidence interval (CI), -11.0 to -0.33;. Leptin may be a primary mediator of exercise-induced improvements in breast cancer recurrence.. This is the first review and meta-analysis to examine combined exercise and caloric restriction programs in breast cancer survivors. Future studies should further examine combined programs and their efficacy for altering leptin.

    Topics: Biomarkers; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Cancer Survivors; Diet, Healthy; Exercise; Female; Humans; Inflammation; Leptin; Neoplasm Recurrence, Local; Weight Loss

2021
Natural Killer Cell Dysfunction in Obese Patients with Breast Cancer: A Review of a Triad and Its Implications.
    Journal of immunology research, 2021, Volume: 2021

    Natural killer cells (NK cells) are a crucial constituent of the innate immune system as they mediate immunity against viruses, bacteria, parasites, and most importantly, tumor cells. The exact mechanism of how the innate immune system and specifically NK cells interact with cancer cells is complex and is yet to be understood. Several factors that constitute the tumor microenvironment (TME) such as hypoxia and TGF-

    Topics: Adipokines; Adipose Tissue; Animals; Breast Neoplasms; Cytokines; Disease Models, Animal; Female; Humans; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Leptin; Lymphocyte Activation; Obesity; Resistin; Tumor Microenvironment

2021
LEP as a potential biomarker in prognosis of breast cancer: Systemic review and meta analyses (PRISMA).
    Medicine, 2021, Aug-20, Volume: 100, Issue:33

    Obesity strongly affects the prognosis of various malignancies, including breast cancer. Leptin (LEP) may be associated with obesity and breast cancer prognosis. The purpose of our study was to determine the prognostic value of LEP in breast cancer.. We conducted a multi-omic analysis to determine the prognostic role of LEP. Different public bioinformatics platforms (Oncomine, Gene Expression Profiling Interactive Analysis, University of California Santa Cruz Xena, bc-GenExMiner, PrognoScan database, R2-Kaplan-Meier Scanner, UALCAN, Search Tool for the Retrieval of Interacting Genes/Proteins database , and The Database for Annotation, Visualization and Integrated Discovery) were used to evaluate the roles of LEP. Clinicopathological variables were evaluated.. LEP was downregulated in breast cancer tissues compared to levels in normal tissues. By co-expressed gene analysis, a positive correlation between LEP and SLC19A3 was observed. Based on the clinicopathological analysis, low LEP expression was associated with older age, higher stage, lymph node status, human epidermal growth factor receptor 2 (HER2) status, estrogen receptor (ER+) positivity, and progesterone receptor (PR+) positivity. Kaplan-Meier survival analysis showed that low LEP expression indicated a poorer prognosis. LEP is hypermethylated in breast cancer tissues in PrognoScan and R2-Kaplan Meier Scanner, and low LEP expression was correlated with poor prognosis. LEP protein-protein interactions were analyzed using Search Tool for the Retrieval of Interacting Genes/Proteins database. Gene ontology analysis results showed that cellular component is mainly associated with the endosome lumen, cytosol, and secretory granules and is upregulated. For the biological process energy reserve, metabolic processes exhibited the greatest regulation compared to the others. In molecular function, it was mainly enriched in a variety of combinations, but hormone activity showed the highest regulation.. Our study provides evidence for the prognostic role of LEP in breast cancer and as a novel potential therapeutic target in such malignancies. Nevertheless, further validation is required.

    Topics: Biomarkers, Tumor; Breast Neoplasms; Correlation of Data; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Middle Aged; Prognosis; Survival Rate

2021
Association of PON1, LEP and LEPR Polymorphisms with Susceptibility to Breast Cancer: A Meta-Analysis.
    Asian Pacific journal of cancer prevention : APJCP, 2021, Aug-01, Volume: 22, Issue:8

    Breast cancer is the most common cancer in American women, except for skin cancers. In this meta-analysis, the associations of polymorphisms within paraoxonase 1 (PON1), leptin (LEP) and leptin receptor (LEPR) genes with susceptibility to breast cancer were comprehensively evaluated.. A universal search in PubMed, Scopus, CNKI, SID, Web of Knowledge and Google Scholar was performed to identify relevant studies up to 01 May, 2021. The strength of the associations was estimated by Odds ratios (ORs) with 95% confidence intervals (95% CIs).. A total of 39 case-control studies including 7 studies with 2005 cases and 2748 controls were on PON1 rs662, 6 studies with 2,031 cases and 1,973 controls on PON1 rs854560, 12 studies with 3,444 cases and 3,583 controls on LEP rs7799039, and 14 studies with 5,330 cases and 6,188 controls on LEPR rs1137101 were selected. Pooled data showed that PON1 rs662 and rs854560 polymorphisms were associated with risk of breast cancer in overall population, but not LEP rs7799039 and LEPR rs1137101.. Our pooled data revealed that the PON1 rs662 and rs854560 polymorphisms were significantly associated with an increased risk of breast cancer in the overall population. However, LEP rs7799039 and LEPR rs1137101 polymorphisms were not associated.

    Topics: Aryldialkylphosphatase; Biomarkers, Tumor; Breast Neoplasms; Female; Genetic Predisposition to Disease; Humans; Leptin; Polymorphism, Single Nucleotide; Prognosis; Receptors, Leptin

2021
The weight of obesity in breast cancer progression and metastasis: Clinical and molecular perspectives.
    Seminars in cancer biology, 2020, Volume: 60

    The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.

    Topics: Biomarkers; Breast Neoplasms; Disease Progression; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Neoplasm Metastasis; Neoplasm Staging; Neovascularization, Pathologic; Obesity

2020
Leptin, Adiponectin, and Sam68 in Bone Metastasis from Breast Cancer.
    International journal of molecular sciences, 2020, Feb-05, Volume: 21, Issue:3

    The most serious aspect of neoplastic disease is the spread of cancer cells to secondary sites. Skeletal metastases can escape detection long after treatment of the primary tumour and follow-up. Bone tissue is a breeding ground for many types of cancer cells, especially those derived from the breast, prostate, and lung. Despite advances in diagnosis and therapeutic strategies, bone metastases still have a profound impact on quality of life and survival and are often responsible for the fatal outcome of the disease. Bone and the bone marrow environment contain a wide variety of cells. No longer considered a passive filler, bone marrow adipocytes have emerged as critical contributors to cancer progression. Released by adipocytes, adipokines are soluble factors with hormone-like functions and are currently believed to affect tumour development. Src-associated in mitosis of 68 kDa (Sam68), originally discovered as a protein physically associated with and phosphorylated by c-Src during mitosis, is now recognised as an important RNA-binding protein linked to tumour onset and progression of disease. Sam68 also regulates splicing events and recent evidence reports that dysregulation of these events is a key step in neoplastic transformation and tumour progression. The present review reports recent findings on adipokines and Sam68 and their role in breast cancer progression and metastasis.

    Topics: Adiponectin; Animals; Bone Neoplasms; Breast Neoplasms; DNA-Binding Proteins; Female; Humans; Leptin; Mitosis; Phosphorylation; RNA-Binding Proteins

2020
The Role of Adipokines in Breast Cancer: Current Evidence and Perspectives.
    Current obesity reports, 2019, Volume: 8, Issue:4

    The current review shows evidence for the role of adipokines in breast cancer (BC) pathogenesis summarizing the mechanisms underlying the association between adipokines and breast malignancy. Special emphasis is given also on intriguing insights into the relationship between obesity and BC as well as on the role of novel adipokines in BC development.. Recent evidence has underscored the role of the triad of obesity, insulin resistance, and adipokines in postmenopausal BC. Adipokines exert independent and joint effects on activation of major intracellular signal networks implicated in BC cell proliferation, growth, survival, invasion, and metastasis, particularly in the context of obesity, considered a systemic endocrine dysfunction characterized by chronic inflammation. To date, more than 10 adipokines have been linked to BC, and this catalog is continuously increasing. The majority of circulating adipokines, such as leptin, resistin, visfatin, apelin, lipocalin 2, osteopontin, and oncostatin M, is elevated in BC, while some adipokines such as adiponectin and irisin (adipo-myokine) are generally decreased in BC and considered protective against breast carcinogenesis. Further evidence from basic and translational research is necessary to delineate the ontological role of adipokines and their interplay in BC pathogenesis. More large-scale clinical and longitudinal studies are awaited to assess their clinical utility in BC prognosis and follow-up. Finally, novel more effective and safer adipokine-centered therapeutic strategies could pave the way for targeted oncotherapy.

    Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Apelin; Breast Neoplasms; Cell Proliferation; Cytokines; Female; Fibronectins; Humans; Inflammation; Leptin; Lipocalin-2; Nicotinamide Phosphoribosyltransferase; Obesity; Oncostatin M; Osteopontin; Resistin

2019
Molecular Links between Central Obesity and Breast Cancer.
    International journal of molecular sciences, 2019, Oct-28, Volume: 20, Issue:21

    Topics: Adiponectin; Adipose Tissue; Breast Neoplasms; Cell Transformation, Neoplastic; Estrogens; Exosome Multienzyme Ribonuclease Complex; Female; Humans; Inflammation; Leptin; Menopause; MicroRNAs; Obesity, Abdominal; Signal Transduction; Tumor Microenvironment

2019
Association of serum leptin with breast cancer: A meta-analysis.
    Medicine, 2019, Volume: 98, Issue:5

    Accumulating evidence has demonstrated that leptin is associated to the tumorigenesis and progression of breast cancer (BC). However, these studies remain inconsistent. Thus, a meta-analysis was conducted to investigate the role of leptin in the patients with BC.. A systematic search in PubMed, Embase, ISI Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases was conducted up to September 1, 2017. The standardized mean difference (SMD) with 95% confidence interval (CI) was applied to pool the effect size. A funnel plot and Egger test were used to evaluate publication bias.. Finally, 43 eligible studies were included in the current meta-analysis. Overall, serum leptin levels in BC cases were significantly higher compared with the controls (SMD = 0.61, P <.0001). When subgroup analyses were restricted to ethnicity and menstrual status, higher serum leptin concentration was also detected in patients with BC. Moreover, BC cases with body mass index (BMI) >25 indicated significantly higher serum leptin levels (SMD = 1.48, P = .034). Furthermore, the BC cases with lymph node metastases showed significantly higher serum leptin concentration (SMD = 0.53, P = .015).. The present meta-analysis suggests that the serum leptin may profiles as a pivotal role in the pathogenesis and metastasis of BC. In addition, leptin will provide useful information for a therapeutic target to treat BC.

    Topics: Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Disease Progression; Ethnicity; Female; Humans; Leptin; Lymphatic Metastasis

2019
The Impact of Obesity on Breast Cancer.
    Current oncology reports, 2018, 04-11, Volume: 20, Issue:6

    The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances-such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden.

    Topics: Adipokines; Adiponectin; Breast Neoplasms; Estrogens; Female; Humans; Inflammation; Leptin; Metabolic Networks and Pathways; Obesity; Receptors, Estrogen; Risk Factors

2018
Leptin Regulation of Cancer Stem Cells in Breast and Gynecologic Cancer.
    Endocrinology, 2018, 08-01, Volume: 159, Issue:8

    It is well established that obesity increases the incidence and worsens the prognosis of women's cancer. For breast cancer, women with obesity exhibit more than a twofold increase in the odds of being diagnosed with cancer, with a greater risk of advanced stage at diagnosis, and ≤40% greater risk of recurrence and death than their normal-weight counterparts. These findings are similar in gynecologic cancers, where women who are obese with a body mass index (BMI) >40 kg/m2 have up to six times greater risk of developing endometrial cancer and a 9.2% increase in mortality with every 10% increase in BMI. Likewise, patients with obesity exhibit a twofold higher risk of premenopausal ovarian cancer, and patients who are obese with advanced stage ovarian cancer have shown a shorter time to recurrence and poorer overall survival. Obesity is accompanied by changes in expression of adipose factors that act on local tissues and systemically. Once obesity was recognized as a factor in cancer incidence and progression, the adipose cytokine (adipokine) leptin became the focus of intense investigation as a putative link, with nearly 3000 publications on the topic. Leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis, and increase therapeutic resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor initiating cells. We will review the literature discussing leptin's role in breast and gynecologic cancer, focusing on its role in CSCs, and consider goals for targeting future therapy in this arena to disrupt tumor initiation and progression in women's cancer.

    Topics: Body Mass Index; Breast Neoplasms; Female; Genital Neoplasms, Female; Humans; Leptin; Mortality; Neoplastic Stem Cells; Obesity; Prognosis

2018
Association between serum leptin levels and breast cancer risk: An updated systematic review and meta-analysis.
    Medicine, 2018, Volume: 97, Issue:27

    Many studies have indicated that leptin is correlated with breast cancer occurrence and tumor behavior. However, this issue remains controversial. Therefore, we conducted an updated meta-analysis to investigate the role of leptin in breast cancer.. We performed a systematic literature search and identified relevant papers up to 1 September 2017. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to evaluate effect sizes.. Thirty-five eligible studies were included in the current meta-analysis. Serum leptin levels were related to breast cancer risk as demonstrated by calculations of the overall SMD = 0.46 (95% CI = 0.31-0.60, I = 93.5%). A subgroup analysis of BMI identified an association between breast cancer and serum leptin levels in patients who are overweight and obese (overweight: SMD = 0.35, 95% CI = 0.13-0.57, I = 88.1%; obesity: SMD = 1.38, 95% CI = 0.64-2.12, I = 89.6%). Additionally, menopausal status subgroup analysis revealed a significant association in postmenopausal women (SMD = 0.26, 95% CI = 0.12-0.40, I = 77.9%). Furthermore, we identified a significant association between breast cancer and serum leptin levels in Chinese women (SMD = 0.61, 95% CI = 0.44-0.79, I = 40.6%).. The results of this meta-analysis suggested that leptin could be a potential biomarker for breast cancer risk in women, especially overweight/obese or postmenopausal women. Therefore, it may be useful for identifying subjects with a high risk for breast cancer who may benefit from preventive treatments.

    Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Leptin; Menopause; Obesity; Overweight; Risk Factors

2018
Signaling Pathways Induced by Leptin during Epithelial⁻Mesenchymal Transition in Breast Cancer.
    International journal of molecular sciences, 2018, Nov-06, Volume: 19, Issue:11

    Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial⁻mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell⁻cell and cell⁻extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides cells with the ability to migrate and invade adjacent or distal tissues, which is a classic feature of invasive or metastatic carcinoma cells. In recent years, the number of cases of breast cancer has increased, making this disease a public health problem worldwide and the leading cause of death due to cancer in women. In this review, we focus on recent advances that establish: (1) leptin as a risk factor for the development of breast cancer, and (2) leptin as an inducer of EMT, an event that promotes tumor progression.

    Topics: Animals; Biomarkers; Breast Neoplasms; Energy Metabolism; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Receptors, Leptin; Signal Transduction; Transcription Factors

2018
Obesity-associated Breast Cancer: Analysis of risk factors.
    Advances in experimental medicine and biology, 2017, Volume: 960

    Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen-plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis.

    Topics: Breast Neoplasms; Cholesterol; Female; Humans; Insulin Resistance; Leptin; Obesity; Risk Factors

2017
Association Between Leptin (-2548G/A) Genes Polymorphism and Breast Cancer Susceptibility: A Meta-Analysis.
    Medicine, 2016, Volume: 95, Issue:4

    Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk. To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country. A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer (A vs G: OR = 1.12, 95%CI = 1.04-1.20, P = 0.002, Phet P < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian (A vs G: OR = 1.11, 95%CI = 1.03-1.20, P = 0.006, Phet = 0.00001). No publication bias was found in the present study. In conclusion, our meta-analysis suggests that the Leptin (-2548G/A) gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian.

    Topics: Alleles; Breast Neoplasms; Female; Genetic Predisposition to Disease; Humans; Leptin; Polymorphism, Single Nucleotide; White People

2016
Leptin, obesity and breast cancer: progress to understanding the molecular connections.
    Current opinion in pharmacology, 2016, Volume: 31

    Obesity has a complicated connection to both breast cancer risk and the clinical behaviour of the established disease. The obese setting provides a unique adipose tissue microenvironment that, in association with systemic endocrine modifications, promotes tumor initiation, primary growth, invasion, and metastatic progression. This review presents an overview of the clinical and experimental evidences highlighting the adipokine leptin as the most important molecular mediator of obesity-breast cancer axis. The research of leptin network operating in this context could launch a new field not only in the knowledge of risk factors for breast cancer but also in the development of leptin targeting drugs as promising anticancer agents.

    Topics: Adipose Tissue; Animals; Antineoplastic Agents; Breast Neoplasms; Disease Progression; Drug Design; Female; Humans; Leptin; Neoplasm Invasiveness; Neoplasm Metastasis; Obesity; Risk Factors

2016
The integrative role of leptin, oestrogen and the insulin family in obesity-associated breast cancer: potential effects of exercise.
    Obesity reviews : an official journal of the International Association for the Study of Obesity, 2015, Volume: 16, Issue:6

    Obesity is an established risk factor for postmenopausal breast cancer. The mechanisms through which obesity influences the development and progression of breast cancer are not fully elucidated; however, several factors such as increased oestrogen, concentrations of various members of the insulin family and inflammation that are associated with adiposity are purported to be important factors in this relationship. Emerging research has also begun to focus on the role of adipokines, (i.e. adipocyte secreted factors), in breast cancer. Leptin secretion is directly related to adiposity and is believed to promote breast cancer directly and independently, as well as through involvement with the oestrogen and insulin signalling pathways. As leptin is secreted from white adipose tissue, any intervention that reduces adiposity may be favourable. However, it is also important to consider that energy expenditure through exercise, independent of fat loss, may improve leptin regulation. The purpose of this narrative review was to explore the role of leptin in breast cancer development and progression, identify key interactions with oestrogen and the insulin family, and distinguish the potential effects of exercise on these interactions.

    Topics: Adiposity; Animals; Breast Neoplasms; Energy Metabolism; Estrogens; Exercise; Female; Humans; Insulin; Insulin Secretion; Leptin; Models, Biological; Molecular Sequence Data; Obesity; Risk Factors; Signal Transduction

2015
Leptin, adipocytes and breast cancer: Focus on inflammation and anti-tumor immunity.
    Life sciences, 2015, Nov-01, Volume: 140

    More than one million new cases of breast cancer are diagnosed worldwide each year and more than 400,000 deaths are caused by the disease. The origin of this pathology is multifactorial and involved genetic, hormonal, environmental and nutritional factors including obesity in postmenopausal women. The role played by the adipose tissue and their secretions, ie adipokines, is beginning to be recognized. Plasma adipokine levels, which are modulated during obesity, could have “remote” effects on mammary carcinogenesis. Breast cancer cells are surrounded and locally influenced by an adipocyte microenvironment, which is probably more extensive in obese people. Hence, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the local pro-inflammatory mechanisms, especially in obese patients, who have increased metastatic potential and greater risk of mortality. This review presents the multifaceted role of leptin in breast cancer development and the different molecular pathways involved such as inflammation, oxidative stress and antitumor immunity.

    Topics: Adipocytes; Breast Neoplasms; Female; Humans; Leptin

2015
Leptin-cytokine crosstalk in breast cancer.
    Molecular and cellular endocrinology, 2014, Jan-25, Volume: 382, Issue:1

    Despite accumulating evidence suggesting a positive correlation between leptin levels, obesity, post-menopause and breast cancer incidence, our current knowledge on the mechanisms involved in these relationships is still incomplete. Since the cloning of leptin in 1994 and its receptor (OB-R) 1 year later by Friedman's laboratory (Zhang et al., 1994) and Tartaglia et al. (Tartaglia et al., 1995), respectively, more than 22,000 papers related to leptin functions in several biological systems have been published (Pubmed, 2012). The ob gene product, leptin, is an important circulating signal for the regulation of body weight. Additionally, leptin plays critical roles in the regulation of glucose homeostasis, reproduction, growth and the immune response. Supporting evidence for leptin roles in cancer has been shown in more than 1000 published papers, with almost 300 papers related to breast cancer (Pubmed, 2012). Specific leptin-induced signaling pathways are involved in the increased levels of inflammatory, mitogenic and pro-angiogenic factors in breast cancer. In obesity, a mild inflammatory condition, deregulated secretion of proinflammatory cytokines and adipokines such as IL-1, IL-6, TNF-α and leptin from adipose tissue, inflammatory and cancer cells could contribute to the onset and progression of cancer. We used an in silico software program, Pathway Studio 9, and found 4587 references citing these various interactions. Functional crosstalk between leptin, IL-1 and Notch signaling (NILCO) found in breast cancer cells could represent the integration of developmental, proinflammatory and pro-angiogenic signals critical for leptin-induced breast cancer cell proliferation/migration, tumor angiogenesis and breast cancer stem cells (BCSCs). Remarkably, the inhibition of leptin signaling via leptin peptide receptor antagonists (LPrAs) significantly reduced the establishment and growth of syngeneic, xenograft and carcinogen-induced breast cancer and, simultaneously decreased the levels of VEGF/VEGFR2, IL-1 and Notch. Inhibition of leptin-cytokine crosstalk might serve as a preventative or adjuvant measure to target breast cancer, particularly in obese women. This review is intended to present an update analysis of leptin actions in breast cancer, highlighting its crosstalk to inflammatory cytokines and growth factors essential for tumor development, angiogenesis and potential role in BCSC.

    Topics: Breast Neoplasms; Cytokines; Female; Humans; Inflammation Mediators; Leptin; Neoplastic Stem Cells; Receptors, Leptin

2014
Breast cancer: major risk factors and recent developments in treatment.
    Asian Pacific journal of cancer prevention : APJCP, 2014, Volume: 15, Issue:8

    Breast cancer is the most common in women worldwide, with some 5-10% of all cases due to inherited mutations of BRCA1 and BRCA2 genes. Obesity, hormone therapy and use of alcohol are possible causes and over-expression of leptin in adipose tissue may also play a role. Normally surgery, radiation therapy and chemotherapy allow a good prognosis where screening measures are in place. New hope in treatment measures include adjuvant therapy, neoadjuvant therapy, and introduction of mono-clonal antibodies and enzyme inhibitors.

    Topics: Adipose Tissue; Alcohol Drinking; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Chemotherapy, Adjuvant; Estrogen Replacement Therapy; Female; Genes, BRCA1; Genes, BRCA2; Humans; Leptin; Mastectomy; Neoadjuvant Therapy; Obesity; Radiotherapy, Adjuvant; Risk Factors; Sedentary Behavior; Selective Estrogen Receptor Modulators

2014
n-3 polyunsaturated fatty acids and mechanisms to mitigate inflammatory paracrine signaling in obesity-associated breast cancer.
    Nutrients, 2014, Oct-30, Volume: 6, Issue:11

    Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA) may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

    Topics: Adiponectin; Aromatase; Breast Neoplasms; Cytokines; Estrogens; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Inflammation; Intra-Abdominal Fat; Leptin; Obesity; Paracrine Communication; Prevalence

2014
[Leptin: Involvement in the pathophysiology of breast cancer].
    Annales d'endocrinologie, 2013, Volume: 74, Issue:2

    More than one million new cases of breast cancer are diagnosed each year worldwide and more than 400,000 deaths occur due to this pathology. Obesity is a risk factor for postmenopausal breast cancer and the place held by the adipose tissue and secretions (i.e. adipokines) begins to be recognized. Indeed, firstly, plasma adipokine levels, modulated in obesity situation, could have effects "remotely" on mammary carcinogenesis and, secondly, breast cancer cells are surrounded by adipocyte microenvironment, which is probably more important in the case of obesity, and may be locally influenced by it. In this context, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the angiogenesis process and local pro-inflammatory mechanisms, especially in obese patients for whom increased metastatic potential and risk of mortality are described.

    Topics: Adipocytes; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Female; Humans; Leptin; Obesity

2013
The Association between Leptin Level and Breast Cancer: A Meta-Analysis.
    PloS one, 2013, Volume: 8, Issue:6

    Contradictory results have been reported regarding the association between leptin level and breast cancer. Therefore, a meta-analysis was performed to investigate this issue.. Published literature from PubMed and the Chinese National Knowledge Infrastructure (CNKI) Database was retrieved. This study was performed based on different cases and control groups. The combined effect ([Formula: see text]) with 95% confidence interval (CI) was calculated using fixed-effects or random-effects model analysis.. Overall, the mean serum leptin level of case groups was significantly higher than that of control groups. A) For 9 studies comparing breast cancer cases and healthy controls the combined effect [Formula: see text] was 0.58 with 95% CI (0.48, 0.68). B) For 4 studies comparing premenopausal breast cancer cases and healthy controls the [Formula: see text] was 0.32 (0.12, 0.52). C) For 5 studies comparing postmenopausal cases and healthy controls the [Formula: see text] was 0.65 (0.46, 0.84). D) For 4 studies comparing breast cancer cases and breast benign controls the [Formula: see text] was 0.38 (0.17, 0.59). E) For 2 studies comparing premenopausal breast cancer cases and breast benign controls the [Formula: see text] was 0.33 (-0.25, 0.91). F) For 6 studies comparing postmenopausal breast cancer cases and breast benign controls the [Formula: see text] was 0.39 (0.19, 0.60). G) For 4 studies comparing lymph node metastasis positive cases and negative controls the [Formula: see text] was 0.72 (0.45, 1.00). H) For 3 studies comparing breast benign cases and healthy controls the [Formula: see text] was 0.71 (0.41, 1.01).. This meta-analysis suggests that leptin level plays a role in breast cancer and has potential for development as a diagnostic tool.

    Topics: Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Lymphatic Metastasis; Prognosis

2013
The biology of leptin and its implications in breast cancer: a general view.
    Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2013, Volume: 33, Issue:12

    Obesity is a world health problem that increases the risk for developing type 2 diabetes, cardiovascular disease, fatty liver, and some types of cancer. In postmenopausal women, it represents an important risk factor for the development of breast cancer (BC). Leptin is an adipokine that is secreted by fatty tissue, and high leptin levels are observed both in mouse models of obesity and in obese subjects. High levels of leptin promote the proliferation and progression of various types of cancer, including BC. This review provides a general overview of the biology of leptin, important laboratory studies, and animal and clinical models that have provided evidence for an active role of leptin in the proliferation, progression, and survival of mammary tumors. Finally, this review addresses the most recent studies on the use of leptin receptor antagonists as a novel therapeutic treatment for BC.

    Topics: Animals; Breast Neoplasms; Disease Models, Animal; Energy Metabolism; Female; Homeostasis; Humans; Leptin; Mice; Molecular Targeted Therapy; Receptors, Leptin; Risk Factors; Signal Transduction

2013
Leptin and adiponectin: emerging therapeutic targets in breast cancer.
    Journal of mammary gland biology and neoplasia, 2013, Volume: 18, Issue:3-4

    Obesity is a recognized risk factor for breast cancer development and poorer response to therapy. Two major fat tissue-derived adipokines, leptin and adiponectin have been implicated in mammary carcinogenesis. Leptin appears to promote breast cancer progression through activation of mitogenic, antiapoptotic, and metastatic pathways, while adiponectin may restrict tumorigenic processes primarily by inhibiting cell metabolism. Furthermore, adiponectin is known to counteract detrimental leptin effects in breast cancer models. Thus, therapeutic inhibition of pro-neoplastic leptin pathways and reactivation of anti-neoplastic adiponectin signaling may benefit breast cancer patients, especially the obese subpopulation. This review focuses on current experimental strategies aiming at leptin and adiponectin pathways in breast cancer models. Novel leptin receptor antagonists and adiponectin receptor agonists as well as other compounds for therapeutic modulation of adipokine pathways are discussed in detail, including potential pharmacological advantages and limitations of these approaches.

    Topics: Adiponectin; Animals; Breast Neoplasms; Female; Humans; Leptin; Molecular Targeted Therapy; Signal Transduction

2013
Control of body weight versus tumorigenesis by concerted action of leptin and estrogen.
    Reviews in endocrine & metabolic disorders, 2013, Volume: 14, Issue:4

    Improper body weight control is most critical to the development of morbid obesity, which is often associated with alternation in leptin (Ob) signaling in the central nervous system. Leptin acts to control fat mass through the regulation of both food intake and energy expenditure. In addition to the primary action in metabolic signaling, leptin has also been found to play a role in reproduction and even in breast tumorigenesis in obese patients. Interestingly, estrogen, a sex hormone, has also been recognized as another crucial factor for energy balance and breast tumorigenesis in obese subjects. Obesity in postmenopausal women has been associated with higher risk of breast cancer. There are substantial data in the literature on the connection of estrogen and leptin pathways in development of obesity and breast cancer. In this review, we discuss the cross-talk of leptin and estrogen signaling pathways in body weight control and breast cancer development.

    Topics: Animals; Body Weight; Breast Neoplasms; Carcinogenesis; Estrogens; Female; Humans; Leptin; Obesity

2013
Multifaceted leptin network: the molecular connection between obesity and breast cancer.
    Journal of mammary gland biology and neoplasia, 2013, Volume: 18, Issue:3-4

    High plasma levels of leptin, a major adipocytokine produced by adipocytes, are correlated with increased fat mass in obese state. Leptin is emerging as a key candidate molecule linking obesity with breast cancer. Acting via endocrine, paracrine, and autocrine manner, leptin impacts various stages of breast tumorigenesis from initiation and primary tumor growth to metastatic progression. Leptin also modulates the tumor microenvironment mainly through supporting migration of endothelial cells, neo-angiogenesis and sustaining recruitment of macrophage and monocytes. Various studies have shown that hyperactive leptin-signaling network leads to concurrent activation of multiple oncogenic pathways resulting in enhanced proliferation, decreased apoptosis, acquisition of mesenchymal phenotype, potentiated migration and enhanced invasion potential of tumor cells. Furthermore, the capability of leptin to interact with other molecular effectors of obese state including, estrogen, IGF-1, insulin, VEGF and inflammatory cytokines further increases its impact on breast tumor progression in obese state. This article presents an overview of the studies investigating the involvement of leptin in breast cancer.

    Topics: Animals; Breast Neoplasms; Female; Humans; Leptin; Obesity; Receptors, Leptin; Risk Factors; Signal Transduction

2013
Integrating leptin and cAMP signalling pathways in triple-negative breast cancer cells.
    Frontiers in bioscience (Landmark edition), 2013, 01-01, Volume: 18, Issue:1

    Breast cancer is a major cause of cancer death in women in the world. Triple-negative breast cancers, which accounts for 10-20% of all mammary tumours, are characterised by an aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer occurrence. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological approaches are warranted. The obesity-linked adipokine, leptin, is a well known mitogen/survival factor in breast cancer cells and several studies have addressed the role of leptin in breast cancer pathogenesis and progression. Surprisingly, recent in vitro studies have shown that leptin enhances the anti-proliferative effects of cAMP elevation in triple-negative breast cancer cells by apoptosis induction. In the current review, we discuss on the role of cAMP as a growth suppressor and of leptin as a growth promoting factor in breast cancer cells and we will focus on the molecular pathways involved in the antiproliferative interaction between leptin and cAMP elevation. The rationale for the possible development of a simple, cheap and innovative approach for therapeutic intervention in triple-negative breast cancer, based on the use of cAMP elevating drugs at lower and tolerable doses, will be also discussed.

    Topics: Breast Neoplasms; Cell Line, Tumor; Cyclic AMP; Drug Resistance, Neoplasm; Female; Humans; Leptin; Signal Transduction; STAT3 Transcription Factor

2013
Leptin and breast cancer: an overview.
    Medical oncology (Northwood, London, England), 2012, Volume: 29, Issue:3

    Leptin is a well-known mediator of obesity. Leptin and its receptor are overexpressed in breast cancer, especially in high-grade tumors. It has an association with progression and poor survival of breast cancer. Leptin can regulate endothelial cell proliferation and promote angiogenesis. There are several other factors such as insulin and HER2 may be involved in the relationship between leptin and breast cancer. Leptin system has emerged as a new and promising therapeutic target for breast cancer. This review article summarizes the current knowledge about the relation of leptin and breast cancer.

    Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Leptin

2012
Leptin and leptin receptor genes in relation to premenopausal breast cancer incidence and grade in Caucasian women.
    Breast cancer research and treatment, 2012, Volume: 131, Issue:1

    Body mass is inversely related to breast cancer risk among premenopausal women. Leptin, an essential cytokine regulating food intake, energy expenditure, glucose, and fat metabolism may be part of the mechanistic pathway. We investigated 50 tagging and candidate SNPs in the leptin (LEP) and leptin receptor (LEPR) genes for associations with premenopausal breast cancer incidence using 405 cases and 810 controls nested within the Nurses' Health Study II. We also examined associations between these SNPs and circulating leptin (among 910 women) and breast cancer grade (among 267 patients). Permutation tests were performed to adjust for multiple testing. We did not detect a significant association between SNPs in the LEP or LEPR gene and either breast cancer incidence or plasma leptin levels. Among cases, 14 SNPs of the LEPR gene were significantly associated with cancer grade, and rs1137101 (Q223R) survived multiple testing adjustment (adjusted P = 0.04). The G carriers of rs1137101 were more likely to have poorly differentiated than well-differentiated cancers. Our data suggest that common genetic variation in the LEP or LEPR gene has no strong association with premenopausal breast cancer risk. The LEPR gene might be associated with breast cancer grade.

    Topics: Adult; Body Mass Index; Body Size; Breast Neoplasms; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Polymorphism, Single Nucleotide; Premenopause; Receptors, Leptin; Risk; White People

2012
Obesity and breast cancer: a clinical biochemistry perspective.
    Clinical biochemistry, 2012, Volume: 45, Issue:3

    To evaluate the laboratory diagnosis aspects of obesity-related health problems with special reference to postmenopausal breast cancer.. We conducted a systemic search of the literature primarily from the PubMed to obtain the relevant data.. Obesity is associated with the dysregulations of a number of body components such as blood constituents, extracellular matrix, and hormones/growth factors axes, which could be utilized for early diagnosis.. Obesity-related disorders including breast cancer have emerged as major health problems in almost all the nations. There is a need to elucidate different biochemical markers that are being used in the clinics or have the potential for such use. A precise understanding of the complex pathologies related with obesity is useful in prevention, early diagnosis and overall clinical management.

    Topics: Biomedical Research; Breast Neoplasms; Female; Humans; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Postmenopause

2012
Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells.
    Biochimica et biophysica acta, 2012, Volume: 1825, Issue:2

    Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e., canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts.

    Topics: Animals; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Leptin; Neoplastic Stem Cells; Receptors, Leptin; Signal Transduction

2012
Adipokine leptin in obesity-related pathology of breast cancer.
    Journal of biosciences, 2012, Volume: 37, Issue:2

    Topics: Animals; Breast Neoplasms; Female; Humans; Leptin; MCF-7 Cells; Mice; Obesity

2012
The balance between leptin and adiponectin in the control of carcinogenesis - focus on mammary tumorigenesis.
    Biochimie, 2012, Volume: 94, Issue:10

    A number of studies indicate that a growing list of cancers may be influenced by obesity. In obese individuals these cancers can be more frequent and more aggressive resulting in reduced survival. One of the most prominent and well characterized cancers in this regard is breast cancer. Obesity plays a complex role in breast cancer and is associated with increased inflammation, angiogenesis and alterations in serum levels of potential growth factors such as insulin, adiponectin, leptin and estrogen. Reduced levels of serum adiponectin have been reported in breast cancer patients compared to healthy controls, particularly in postmenopausal women and the level of adiponectin has been shown to be inversely associated with insulin resistance. The role of serum leptin levels in breast cancer appears to be more complex. Some studies have shown leptin to be increased in women with breast cancer but other studies have found leptin to be decreased or unchanged. This may be due to a number of confounding issues. We and others propose that it may be the levels of adiponectin and leptin as well as the balance of adiponectin and leptin that are the critical factors in breast and other obesity related cancer tumorigenesis. This review will focus on the current understanding of the interplay between obesity and the functions of leptin and adiponectin. It will then examine what is known about their potential roles in cancer particularly as pertains to breast cancer and how the ratio of adiponectin to leptin may play a role in tumorigenesis.

    Topics: Adiponectin; Animals; Breast Neoplasms; Humans; Leptin; Mammary Neoplasms, Animal

2012
Molecular mechanisms of leptin and adiponectin in breast cancer.
    European journal of cancer (Oxford, England : 1990), 2011, Volume: 47, Issue:1

    Obesity is associated with an increased risk of breast cancer in postmenopausal women. Accumulating evidence suggests that adipose tissue, which is an endocrine organ producing a large range of factors, may interfere with breast cancer development. Leptin and adiponectin are two major adipocyte-secreted hormones. The pro-carcinogenic effect of leptin and conversely, the anti-carcinogenic effect of adiponectin result from two main mechanisms: a modulation in the signalling pathways involved in proliferation process and a subtle regulation of the apoptotic response. This review provides insight into recent findings on the molecular mechanisms of leptin and adiponectin in mammary tumours, and discusses the potential interplay between these two adipokines in breast cancer.

    Topics: Adiponectin; Adipose Tissue; Animals; Breast Neoplasms; Cell Communication; Female; Humans; Leptin; Mice; Obesity; Receptors, Leptin; Tumor Cells, Cultured

2011
Associations between adipokines and obesity-related cancer.
    Frontiers in bioscience (Landmark edition), 2011, 01-01, Volume: 16, Issue:5

    There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.

    Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Colorectal Neoplasms; Endometrial Neoplasms; Esophageal Neoplasms; Female; Humans; Kidney Neoplasms; Leptin; Male; Neoplasms; Obesity; Pancreatic Neoplasms; Prostatic Neoplasms; Thyroid Neoplasms

2011
Polymorphisms in three obesity-related genes (LEP, LEPR, and PON1) and breast cancer risk: a meta-analysis.
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2011, Volume: 32, Issue:6

    Common genetic variations in the leptin (LEP), leptin receptor (LEPR), and paraoxonase 1 (PON1) genes have been considered to be implicated in the development of breast cancer. However, the results were inconsistent. In this study, a meta-analysis was performed to assess the associations of five polymorphisms, including LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, and PON1 Q192R polymorphisms, with breast cancer risk. Published literature from PubMed, ISI Web of Science, Embase databases, CNKI, and Wanfang Data were retrieved. All studies evaluating the association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, PON1 L55M, or PON1 Q192R polymorphism and breast cancer risk were included. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Three studies (2,003 cases and 1,967 controls) for LEP G2548A polymorphism, nine studies (4,627 cases and 5,476 controls) for LEPR Q223R polymorphism, five studies (2,759 cases and 2,573 controls) for LEPR Lys109Arg polymorphism, four studies (1,517 cases and 1,379 controls) for PON1 L55M polymorphism, and five studies (1,575 cases and 2,283 controls) for PON1 Q192R polymorphism were included in the meta-analysis. Overall, the results showed null significant association between LEP G2548A, LEPR Q223R, LEPR Lys109Arg, or PON1 Q192R polymorphism and breast cancer risk; however, PON1 L55M was significantly associated with breast cancer risk overall (MM vs. LL: OR = 2.16; 95% CI, 1.76-2.66). For LEPR Q223R polymorphism, further subgroup analysis suggested that the association was only statistically significant in East Asians (OR = 0.50; 95% CI, 0.36-0.70) but not in Caucasians (OR = 1.06; 95% CI, 0.77-1.45) or Africans (OR = 1.30; 95% CI, 0.83-2.03). The present meta-analysis suggested that LEPR Q223R polymorphism might be implicated in the development of breast cancer in East Asians; PON1 L55M might increase breast cancer risk. However, given the limited sample size, the findings warrant further investigation.

    Topics: Aryldialkylphosphatase; Asian People; Breast Neoplasms; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Obesity; Odds Ratio; Polymorphism, Genetic; Receptors, Leptin; Risk Assessment; Risk Factors; White People

2011
The multifactorial role of leptin in driving the breast cancer microenvironment.
    Nature reviews. Endocrinology, 2011, Nov-15, Volume: 8, Issue:5

    Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed.

    Topics: Breast Neoplasms; Female; Humans; Leptin; Receptors, Leptin; Signal Transduction

2011
Effect of obesity on breast cancer development.
    Veterinary pathology, 2010, Volume: 47, Issue:2

    In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models.

    Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Estrogens; Female; Humans; Leptin; Mice; Obesity; Receptors, Estrogen

2010
Leptin as a potential therapeutic target for breast cancer prevention and treatment.
    Expert opinion on therapeutic targets, 2010, Volume: 14, Issue:4

    Obesity is considered to be an important risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, can also affect breast cancer development. Leptin is one of the adipokines that is measured in serum/plasma in increasing amounts as body weight/body fat increases.. We highlight important aspects of leptin in relationship to mammary/breast tumor development. This includes findings from human, in vitro and animal studies. Information on leptin-related compounds which may have therapeutic use is presented. Additionally strategies to alter serum leptin levels by dietary and pharmacological interventions are discussed.. The reader will gain insights into the relationship of an adipose tissue protein and its potential role in breast cancer development as well as ways to intervene in leptin's actions.. Continued research will determine if interfering with the action of leptin has preventive or therapeutic applications in breast cancer.

    Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Leptin; Mammary Neoplasms, Experimental; Obesity

2010
Obesity and breast cancer: status of leptin and adiponectin in pathological processes.
    Cancer metastasis reviews, 2010, Volume: 29, Issue:4

    It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.

    Topics: Adiponectin; Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Progression; Female; Humans; Leptin; Obesity

2010
IL-1 family in breast cancer: potential interplay with leptin and other adipocytokines.
    FEBS letters, 2009, Jan-22, Volume: 583, Issue:2

    Obesity is associated with an increased risk of breast cancer. interleukin-1 (IL-1), a pro-inflammatory cytokine secreted by adipose tissue, is involved in breast cancer development. There is also convincing evidence that other adipocytokines including leptin not only have a role in haematopoiesis, reproduction and immunity but are also growth factors in cancer. Therefore, IL-1 family and leptin family are adipocytokines which could represent a major link between obesity and breast cancer progression. This minireview provides insight into recent findings on the prognostic significance of IL-1 and leptin in mammary tumours, and discusses the potential interplay between IL-1 family members and adipocyte-derived hormones in breast cancer.

    Topics: Adipokines; Breast Neoplasms; Female; Humans; Interleukin-1; Leptin; Obesity

2009
Targeting the adiponectin:leptin ratio for postmenopausal breast cancer prevention.
    Frontiers in bioscience (Scholar edition), 2009, 06-01, Volume: 1, Issue:1

    Obesity is a risk factor for postmenopausal breast cancer. Elevated estrogen levels are thought to be a growth factor associated with this relationship. However, there is increasing evidence that factors produced directly in adipose tissue, adipokines, specifically adiponectin and leptin, impact breast cancer development. Serum adiponectin levels are reduced in women diagnosed with breast cancer and in vitro studies using human breast cancer cell lines have shown antiproliferative action of adiponectin. In contrast, elevated serum leptin levels were associated with breast cancer in some studies. In mice which lack the leptin receptor or are leptin deficient oncogene-induced mammary tumors were not detected while leptin enhanced proliferation of breast cancer cell lines, particularly those that express estrogen receptors. Of particular interest, one recent study reported that the adiponectin:leptin ratio was reduced in women with breast cancer. Here we speculate that the ratio of these adipokines may be more important in breast cancer than their absolute concentrations. Additionally, we propose strategies to alter this ratio and thus provide protection against the development of breast cancer.

    Topics: Adiponectin; Animals; Breast Neoplasms; Female; Humans; Leptin; Postmenopause

2009
Angiogenesis, adipokines and breast cancer.
    Cytokine & growth factor reviews, 2009, Volume: 20, Issue:3

    The prevalence of overweight and obesity is rapidly increasing world wide. Numerous epidemiological studies have shown that obesity is a risk factor for postmenopausal breast cancer and relapse. However, the biological factors that drive the growth and progression of these tumors and how obesity contributes to the tumor microenvironment are poorly understood. Tumor development and metastasis are dependent on the process of angiogenesis or the formation of new blood vessels. More importantly, a ready supply of adipose tissue-derived angiogenic adipokines, notably VEGF and leptin, and the production of inflammatory cytokines by infiltrating macrophages that occurs in adipose tissues with obesity, promotes the paracrine stimulation of vascular endothelial cell growth needed for adipogenesis, while maintaining a microenvironment that is favorable for breast tumorigenesis.

    Topics: Adipokines; Adipose Tissue; Breast Neoplasms; Cytokines; Female; Humans; Leptin; Models, Biological; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A

2009
Adolescent obesity and puberty: the "perfect storm".
    Annals of the New York Academy of Sciences, 2008, Volume: 1135

    Obesity is the most serious long-term health risk currently facing America's adolescents. Weight gain during adolescence carries a higher risk for adult obesity and the metabolic syndrome. This review highlights early adolescence as a particularly high-risk time for weight gain due to the synergy of naturally occurring metabolic changes along with increasing behavioral risk factors. One of the first potential health effects of abnormal weight gain during this period is earlier puberty, usually manifested as thelarche. The obesity epidemic is clearly implicated in the national trend toward earlier thelarche, although the data are not as strong in relation to menarche. Leptin activation of the hypothalamic-pituitary axis, combined with insulin resistance, and increased adiposity may result in the higher estrogen levels that are linked to breast development. Young adolescents also experience a sharp decline in their level of physical activity, worsening nutritional habits, and other important psychosocial and developmental risk factors that may contribute to obesity and estrogen-dependent disease in later life, including polycystic ovary syndrome and breast cancer. Unfortunately, the very psychosocial factors that contribute to abnormal weight gain during early adolescence make prevention and treatment in this population particularly challenging. Therefore, intervening prior to pubertal onset becomes even more important given the risk factors present once puberty begins.

    Topics: Adolescent; Adult; Breast Neoplasms; Estrogens; Female; Humans; Hypothalamo-Hypophyseal System; Insulin Resistance; Leptin; Metabolic Syndrome; Obesity; Polycystic Ovary Syndrome; Puberty; Risk Factors; Weight Gain

2008
Leptin signaling in breast cancer: an overview.
    Journal of cellular biochemistry, 2008, Nov-01, Volume: 105, Issue:4

    The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.

    Topics: Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Receptors, Leptin; Signal Transduction

2008
Obesity hormone leptin: a new target in breast cancer?
    Breast cancer research : BCR, 2007, Volume: 9, Issue:1

    Leptin is a multifunctional hormone produced mainly by the adipose tissue and involved in the regulation of food intake and energy balance. In addition, leptin can stimulate mitogenic and angiogenic processes in peripheral organs. Because leptin levels are elevated in obese individuals and excess body weight has been shown to increase breast cancer risk in postmenopausal women, attempts have been made to evaluate whether leptin can promote breast cancer. Data obtained in cell and animal models and analyses of human breast cancer biopsies indeed suggest such an involvement. Furthermore, a recent report clearly shows that targeting leptin signaling may reduce mammary carcinogenesis. Thus, leptin should become a new attractive target in breast cancer.

    Topics: Animals; Breast Neoplasms; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Humans; Leptin; Neovascularization, Pathologic; Signal Transduction

2007
Mechanisms of disease: adipokines and breast cancer - endocrine and paracrine mechanisms that connect adiposity and breast cancer.
    Nature clinical practice. Endocrinology & metabolism, 2007, Volume: 3, Issue:4

    A vast number of epidemiological studies suggest an important, but still controversial, role for obesity and adipose tissue mass in breast cancer risk and an association with tumor phenotype. The main conclusions from these studies raise the possibility that the adipose tissue can act as an effector organ that influences both cancer risk and tumor behavior. Here we also review heterotypic mechanisms in breast-cancer tumorigenesis; these mechanisms involve soluble secreted factors from peritumoral cells, extracellular-matrix components and interactions between stromal cells and tumor cells that create a specific and local peritumoral microenvironment. As a special focus, we discuss the increasing evidence for a role of peritumoral adipose tissue and secreted adipokines (such as adiponectin and leptin) in breast cancer; furthermore, the cellular and molecular basis of the peritumoral 'desmoplastic' tissue reaction observed in breast cancer is reviewed in detail.

    Topics: Adiponectin; Adipose Tissue; Adiposity; Breast Neoplasms; Endocrine System; Female; Humans; Leptin; Models, Biological; Paracrine Communication; Risk Factors

2007
Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression.
    Endocrine-related cancer, 2007, Volume: 14, Issue:2

    Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk. In this review, we discuss the direct and indirect effects of these protein factors on the biological and clinical aspects of breast cancer biology, and emphasize their distinctive modes of action through endocrine-, paracrine-, and autocrine-mediated pathways. The stimulatory effects of leptin on breast cancer growth were considered to occur primarily via activation of the estrogen receptor; however, new evidence suggests that leptin may be acting on downstream cell signaling pathways in both estrogen-dependent and -independent cell types. Another secretory adipokine, HGF, may act largely not only to promote tumor cell invasion, but also to enhance tumor growth indirectly by stimulating angiogenesis. In contrast, adiponectin, an endogenous insulin sensitizer, exerts a direct growth-inhibitory effect on tumor cells by downregulating cell proliferation and upregulating apoptosis, and also inhibits tumor-related angiogenesis.

    Topics: Adiponectin; Autocrine Communication; Breast Neoplasms; Disease Progression; Female; Hepatocyte Growth Factor; Humans; Leptin; Paracrine Communication; Risk

2007
Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.
    Obesity reviews : an official journal of the International Association for the Study of Obesity, 2007, Volume: 8, Issue:5

    Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.

    Topics: Adiponectin; Body Composition; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Metabolic Syndrome; Obesity; Risk Factors

2007
Adipocytokines and cancer.
    Physiological research, 2006, Volume: 55, Issue:3

    Adipose tissue-produced hormones significantly affect the metabolism of lipids and carbohydrates as well as numerous other processes in human body. It is generally accepted that endocrine dysfunction of adipose tissue may represent one of the causal links between obesity and insulin resistance/diabetes. Epidemiological studies underlined that obesity represents a significant risk factor for the development of cancer, although the exact mechanism of this relationship remains to be determined. Multiple recent studies have indicated that some of adipose tissue-derived hormones may significantly influence the growth and proliferation of tumorous stroma and malignant cells within. Here we review current knowledge about possible relationship of leptin and adiponectin to the etiopathogenesis of different malignant tumors. Most of the studies indicated that while leptin may potentiate the growth of cancer cells in vitro, adiponectin appears to have an opposite effect. Further studies are necessary to decide whether obesity-induced endocrine dysfunction of adipose tissue can directly influence carcinogenesis in different tissues and organs.

    Topics: Adiponectin; Adipose Tissue; Breast Neoplasms; Female; Humans; Leptin; Male; Neoplasms; Prostatic Neoplasms

2006
Energy balance adiposity and breast cancer - energy restriction strategies for breast cancer prevention.
    Obesity reviews : an official journal of the International Association for the Study of Obesity, 2006, Volume: 7, Issue:1

    Excess adiposity over the pre- and postmenopausal years is linked to risk of postmenopausal breast cancer. Weight loss could potentially reduce risk amongst those with excess weight via beneficial effects on the hormonal (decreased circulating levels of oestradiol, testosterone, insulin) and secretory profiles of adipocytes (decreased production of leptin, tumour necrosis factor-alpha, interleukin 6 and increased production of adiponectin). Only modest reductions in adipose tissue are achieved and sustained with current weight loss programmes, which makes strategies to mitigate the adverse metabolic effect of adiposity a priority for cancer prevention. The adverse hormonal and secretory effects of adipose tissue are influenced substantially by acute changes in energy balance prior to changes in adiposity. Human and animal studies have shown dietary energy restriction to bring about favourable changes in circulating levels of insulin, leptin, sex hormone binding globulin, insulin-like growth factor-1, oestradiol, testosterone, reactive oxygen species, and the production and secretion of locally acting adipokines and inflammatory cytokines, that is, increased adiponectin and decreased interleukin-6. Achieving and sustaining energy restriction remains a difficult challenge. Intermittent energy restriction is a potential strategy for promoting periods of energy restriction on a long-term basis. Animal and human data suggest that intermittent energy restriction may have cancer preventative effects beyond that of chronic energy restriction and weight loss. Intermittent energy restriction may be a potential strategy for the primary prevention of breast cancer.

    Topics: Adiponectin; Adipose Tissue; Androgens; Animals; Breast Neoplasms; Cytokines; Energy Intake; Energy Metabolism; Female; Gonadal Steroid Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Obesity; Oxidation-Reduction; Reactive Oxygen Species; Sex Hormone-Binding Globulin

2006
Leptin--from regulation of fat metabolism to stimulation of breast cancer growth.
    Pathology oncology research : POR, 2006, Volume: 12, Issue:2

    Leptin restricts intake of calories as a satiety hormone. It probably stimulates neoplastic proliferation in breast cancer, too. Growth of malignant cells could be regulated by various leptin-induced second messengers like STAT3 (signal transducers and activators of transcription 3), AP-1 (transcription activator protein 1), MAPK (mitogen-activated protein kinase) and ERKs (extracellular signal-regulated kinases). They seem to be involved in aromatase expression, generation of estrogens and activation of estrogen receptor alpha (ERalpha) in malignant breast epithelium. Leptin may maintain resistance to antiestrogen therapy. Namely, it increased activation of estrogen receptors, therefore, it was suspected to reduce or even overcome the inhibitory effect of tamoxifen on breast cell proliferation. Although several valuable reviews have been focused on the role of leptin in breast cancer, the status of knowledge in this field changes quickly and our insight should be continuously revised. In this summary, we provide refreshed interpretation of intensively reported scientific queries of the topic.

    Topics: Animals; Breast Neoplasms; Cell Proliferation; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Estrogen Receptor Modulators; Estrogens; Humans; Leptin; Lipid Metabolism; Obesity

2006
Leptin is a growth factor in cancer.
    The Journal of surgical research, 2004, Volume: 116, Issue:2

    Topics: Adipocytes; Animals; Anorexia; Breast Neoplasms; Cell Differentiation; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Growth Substances; Humans; Leptin; Leukemia; Male; Neoplasms; Prostatic Neoplasms

2004
The role of leptin in breast cancer.
    European journal of gynaecological oncology, 2004, Volume: 25, Issue:2

    Leptin, the protein hormone produced mainly by adipocytes, placenta and mammary epithelium plays a significant role in, e.g., control of metabolism, reproductive processes, immune processes, angiogenesis, haemopoiesis and oxidation of lipids. Since some authors link leptin to mechanisms of mammary cancer development, the clinical data has been screened to allow evaluation of the hypothesis.

    Topics: Breast Neoplasms; Female; Humans; Leptin

2004
Obesity, adipocytokines, and insulin resistance in breast cancer.
    Obesity reviews : an official journal of the International Association for the Study of Obesity, 2004, Volume: 5, Issue:3

    The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.

    Topics: Adipocytes; Adiponectin; Animals; Body Composition; Breast Neoplasms; Cytokines; Female; Humans; Insulin; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Leptin; Obesity; Prognosis; Proteins; Risk Factors

2004
Breast cancer and obesity: an update.
    Nutrition and cancer, 2003, Volume: 45, Issue:1

    Obesity has a complicated relationship to both breast cancer risk and the clinical behavior of the established disease. In postmenopausal women, particularly the elderly, various measures of obesity have been positively associated with risk. However, before menopause increased body weight is inversely related to breast cancer risk. In both premenopausal and postmenopausal breast cancer, the mechanisms by which body weight and obesity affect risk have been related to estrogenic activity. Obesity has also been related to advanced disease at diagnosis and with a poor prognosis in both premenopausal and postmenopausal breast cancer. Breast cancer in African-American women, considering its relationship to obesity, exhibits some important differences from those described in white women, although the high prevalence of obesity in African-American women may contribute to the relatively poor prognosis compared with white American women. Despite the emphasis on estrogens to explain the effects of obesity on breast cancer, other factors may prove to be equally or more important, particularly as they relate to expression of an aggressive tumor phenotype. Among these, this review serves to stress insulin, insulin-like growth factor-I, and leptin, and their relationship to angiogenesis, and transcriptional factors.

    Topics: Breast Neoplasms; Estrogens; Ethnicity; Female; Humans; Insulin; Leptin; Menopause; Obesity; Prognosis; Risk Factors; Somatomedins

2003
Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin (review).
    International journal of oncology, 2002, Volume: 21, Issue:6

    Leptin is a hormone with multiple biological actions which is produced predominantly by adipose tissue; in humans, plasma levels correlate with total body fat, and particularly high concentrations occur in obese women. Several actions of leptin, including the stimulation of normal and tumor cell growth, migration and invasion, and enhancement of angiogenesis, suggest that this hormone can promote an aggressive breast cancer phenotype which can be estrogen-independent. This effect may involve activation of the transcription factor NFkappaB. Leptin can also induce aromatase activity, with the potential for the promotion of estrogen production from androstenedione in adipose tissue, and hence the stimulation of estrogen-dependent breast cancer progression. On this basis, we hypothesize that leptin, perhaps in association with insulin, the plasma concentrations of which correlate with those of leptin, has an important role in the known adverse effect of obesity on breast cancer.

    Topics: Animals; Aromatase; Breast Neoplasms; Female; Humans; Insulin; Leptin; NF-kappa B; Obesity; Signal Transduction

2002

Trials

23 trial(s) available for leptin and Breast-Neoplasms

ArticleYear
Randomized trial of exercise on cancer-related blood biomarkers and survival in women with ovarian cancer.
    Cancer medicine, 2023, Volume: 12, Issue:14

    In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer-related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer.. This secondary analysis of a published randomized controlled trial examined the impact of a 6-month exercise intervention versus attention-control on change in prespecified circulating biomarkers (cancer antigen 125 (CA-125), C-reactive protein (CRP), insulin-like growth factor-1(IGF-1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention-control on all-cause mortality included all (N = 144) participants. All statistical tests were two-sided.. Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post-diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF-1 (group difference in change: -14.2 (-26.1 to -2.3) ng/mL (least squared means (95% CI))) and leptin (-8.9 (-16.5 to -1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention-control (N = 51). No group difference in change was seen for CA-125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow-up of 70 months [range 6.6-105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention-control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99).. Further studies are needed to determine the clinical significance of exercise-induced changes in cancer-related circulating biomarkers in women with ovarian cancer.

    Topics: Biomarkers; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Ovarian Neoplasms

2023
[Leptin promotes the proliferation and migration of MDA-MB-231 breast cancer cells by up regulating MMP14].
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2022, Volume: 38, Issue:1

    Objective To investigate the effect of matrix metalloproteinase 14 (MMP14) on the proliferation and migration of MDA-MB-231 human breast cancer cells treated with leptin. Methods MDA-MB-231 breast cancer cells were randomly divided into control group and (50, 100, 200, 400) ng/mL leptin treated groups. Real-time fluorescence quantitative PCR and Western blot were used to detect the expressions of MMP14 mRNA and protein in cancer cells. The MMP14 of MDA-MB-231 cells and leptin receptor genes were silenced and the silenced cells were stimulated with different concentrations of leptin, then cell proliferation was detected by MTT assay, cell migration was detected by scratch assay, and MMP14 protein expression was detected by Western blot. Results Compared with those in the control group, the mRNA and protein expressions of MMP14 increased in a dose-dependent manner in leptin treated groups. After knockdown of MMP14 and leptin receptor genes, the promoting effect of leptin on the proliferation and migration of MDA-MB-231 cells and the expression of MMP14 protein were weakened. Conclusion Leptin up-regulates the expression of MMP14 in MDA-MB-231 cells and promotes cell proliferation and migration.

    Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Matrix Metalloproteinase 14

2022
Effects of decaffeinated green coffee extract supplementation on anthropometric indices, blood glucose, leptin, adiponectin and neuropeptide Y (NPY) in breast cancer survivors: a randomized clinical trial.
    Food & function, 2022, Oct-03, Volume: 13, Issue:19

    Topics: Adiponectin; Adolescent; Adult; Aged; Blood Glucose; Body Mass Index; Breast Neoplasms; Cancer Survivors; Dietary Supplements; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Neuropeptide Y; Obesity; Young Adult

2022
Lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients: the potential role of the adipokine leptin.
    Breast cancer research and treatment, 2021, Volume: 190, Issue:3

    The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known "lack of cross-resistance".. Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using Luminex xMAP technology (multiple ELISA).. Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo.. Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with the non-steroidal aromatase inhibitor letrozole. Our findings provide new insights into the influence of clinically important aromatase inhibitors on cytokine levels in vivo that contribute to the understanding of the clinically observed lack of cross-resistance between non-steroidal and steroidal aromatase inhibitors in breast cancer patients.. Registered on March 23rd 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

    Topics: Adipokines; Androstadienes; Aromatase Inhibitors; Breast Neoplasms; Female; Humans; Leptin; Letrozole; Nitriles

2021
Psychological distress among health care professionals of the three COVID-19 most affected Regions in Cameroon: Prevalence and associated factors.
    Annales medico-psychologiques, 2021, Volume: 179, Issue:2

    The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

    Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Estrogen Receptor Modulators; Europe; Evoked Potentials, Auditory, Brain Stem; Exosomes; Feasibility Studies; Female; Ferricyanides; Ferrocyanides; Fibrinogen; Finite Element Analysis; Fistula; Fluorescent Dyes; Fluorides, Topical; Fluorodeoxyglucose F18; Fluticasone; Follow-Up Studies; Food Contamination; Food Microbiology; Foods, Specialized; Forensic Medicine; Frail Elderly; France; Free Radicals; Fresh Water; Fungi; Fungicides, Industrial; Galactosamine; Gastrointestinal Neoplasms; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Frequency; Genetic Predisposition to Disease; Genotype; Gingival Hemorrhage; Glioblastoma; Glioma; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucose; Glucose Transport Proteins, Facilitative; Glucosides; Glutamine; Glycolysis; Gold; GPI-Linked Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Graphite; Haplotypes; HCT116 Cells; Healthy Volunteers; Hearing Loss; Heart Failure; Hedgehog Proteins; HEK293 Cells; HeLa Cells; Hemodynamics; Hemorrhage; Hepatocytes; Hippo Signaling Pathway; Histone Deacetylases; Homeostasis; Hospital Mortality; Hospitalization; Humans; Hydantoins; Hydrazines; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Hydroxylamines; Hypoglycemic Agents; Immunity, Innate; Immunoglobulin G; Immunohistochemistry; Immunologic Factors; Immunomodulation; Immunophenotyping; Immunotherapy; Incidence; Indazoles; Indonesia; Infant; Infant, Newborn; Infarction, Middle Cerebral Artery; Inflammation; Injections, Intramuscular; Insecticides; Insulin-Like Growth Factor I; Insurance, Health; Intention to Treat Analysis; Interleukin-1 Receptor-Associated Kinases; Interleukin-6; Intrauterine Devices; Intrauterine Devices, Copper; Iron; Ischemia; Jordan; Keratinocytes; Kidney; Kidney Diseases; Kir5.1 Channel; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Laparoscopy; Lasers; Lasers, Semiconductor; Lenalidomide; Leptin; Lethal Dose 50; Levonorgestrel; Limit of Detection; Lipid Metabolism; Lipid Metabolism Disorders; Lipogenesis; Lipopolysaccharides; Liquid Biopsy; Liver; Liver Abscess, Pyogenic; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Longevity; Lung Neoplasms; Luteolin; Lymph Nodes; Lymphocyte Activation; Macaca fascicularis; Macrophages; Mad2 Proteins; Magnetic Resonance Imaging; Male; Mammary Glands, Human; Manganese; Manganese Compounds; MAP Kinase Signaling System; Materials Testing; Maternal Health Services; MCF-7 Cells; Medicaid; Medicine, Chinese Traditional; Melanoma; Membrane Proteins; Mental Health; Mercury; Metal Nanoparticles; Metals, Heavy; Metformin; Methionine Adenosyltransferase; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Nude; Microalgae; Microbial Sensitivity Tests; Microglia; MicroRNAs; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Mitochondria; Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen Isotopes; Pancreas; Pancreaticoduodenectomy; Pandemics; Particle Size; Particulate Matter; Patient Acceptance of Health Care; Patient Compliance; PC-3 Cells; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Periodontitis; Peroxides; Peru; Pest Control, Biological; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phylogeny; Pilot Projects; Piperidines; Plant Bark; Plant Extracts; Plant Leaves; Plasmids; Platelet Function Tests; Pneumonia, Viral; Podocytes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Terephthalates; Polymers; Polymorphism, Single Nucleotide; Porosity; Portugal; Positron-Emission Tomography; Postoperative Complications; Postural Balance; Potassium Channels, Inwardly Rectifying; Povidone; Powders; Precancerous Conditions; Precision Medicine; Predictive Value of Tests; Pregnancy; Prenatal Care; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prostatectomy; Prostatic Neoplasms; Proteasome Inhibitors; Protective Agents; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein Transport; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Psychiatric Nursing; PTEN Phosphohydrolase; Pulmonary Embolism; Pyrimethamine; Radiopharmaceuticals; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Receptor, ErbB-2; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, G-Protein-Coupled; Recombinational DNA Repair; Recovery of Function; Regional Blood Flow; Renal Dialysis; Renin; Renin-Angiotensin System; Reperfusion Injury; Reproducibility of Results; Republic of Korea; Respiratory Distress Syndrome; Retrospective Studies; Rhodamines; Risk Assessment; Risk Factors; RNA, Long Noncoding; RNA, Messenger; Running; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salinity; Salmeterol Xinafoate; Sarcoma; Seasons; Shoulder Injuries; Signal Transduction; Silicon Dioxide; Silver; Sirtuin 1; Sirtuins; Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

2021
Skin carotenoids are inversely associated with adiposity in breast cancer survivors.
    Nutrition research (New York, N.Y.), 2020, Volume: 79

    Carotenoids are antioxidants which may mitigate some of the adverse effects of obesity, a condition associated with poor outcomes in breast cancer patients. We hypothesized that baseline skin carotenoids would be inversely associated with adiposity in breast cancer survivors and would increase with weight loss. Skin carotenoid score (SCS) was assessed by resonance Raman spectroscopy in breast cancer survivors (body mass index ≥25 kg/m

    Topics: Adiposity; Biomarkers; Breast Neoplasms; C-Reactive Protein; Cancer Survivors; Carotenoids; Diet; Female; Humans; Leptin; Middle Aged; Obesity; Skin; Weight Reduction Programs

2020
Association between changes in fat distribution and biomarkers for breast cancer.
    Endocrine-related cancer, 2017, Volume: 24, Issue:6

    We assessed the associations between changes in total and abdominal fat and changes in biomarkers for breast cancer risk using data of the SHAPE-2 trial. In the SHAPE-2 trial, 243 postmenopausal overweight women were included. The intervention in this trial consisted of 5-6 kg weight loss either by diet only or exercise plus diet. After 16 weeks, we measured serum sex hormones, inflammatory markers, total body fat (measured by DEXA scan) and intra and subcutaneous abdominal fat (measured by MRI). Associations between changes in different body fat depots and biomarkers were analysed by linear regression using the study cohort irrespective of randomisation to make maximal use of the distribution of changes in fat measures. We found that a loss in total body fat was associated with favourable changes in free oestradiol, free testosterone, leptin and sex hormone binding globulin (SHBG). The loss of intra-abdominal fat was associated with a decrease in free testosterone, hsCRP and leptin, and an increase in SHBG. In the multivariable analysis, the best fitted models for the biomarkers free oestradiol, SHBG leptin and adiponectin included only total body fat. For free testosterone, this was subcutaneous abdominal fat, and for hsCRP and IL-6, only intra-abdominal fat change was important. For IL-6 and adiponectin, however, associations were weak and not significant. We conclude that, in our population of healthy overweight postmenopausal women, loss of fat at different body locations was associated with changes in different types of biomarkers, known to be related to risk of breast cancer.

    Topics: Adiponectin; Adipose Tissue; Aged; Biomarkers; Body Fat Distribution; Breast Neoplasms; C-Reactive Protein; Diet; Estradiol; Exercise; Female; Humans; Interleukin-6; Leptin; Middle Aged; Overweight; Postmenopause; Risk Factors; Sex Hormone-Binding Globulin; Testosterone; Weight Loss

2017
Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2016, Volume: 25, Issue:8

    Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer.. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up.. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose).. In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat.. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR.

    Topics: Adiponectin; Adipose Tissue; Adult; Body Composition; Breast; Breast Neoplasms; Case-Control Studies; Exercise; Exercise Movement Techniques; Female; Humans; Leptin; Physical Fitness; Premenopause; Risk; Surveys and Questionnaires

2016
Phase II study of metformin for reduction of obesity-associated breast cancer risk: a randomized controlled trial protocol.
    BMC cancer, 2016, 07-19, Volume: 16

    Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk.. This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n = 75) or placebo (n = 75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored.. The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.. ClinicalTrials.gov Identifier: NCT02028221 . Registered on January 2, 2014. Grant #: 1R01CA172444-01A1 awarded on Sept 11, 2013.

    Topics: Adiponectin; Adult; Body Weight; Breast; Breast Neoplasms; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Magnetic Resonance Imaging; Metformin; Middle Aged; Obesity; Outcome Assessment, Health Care; Risk Factors; Testosterone; Waist Circumference

2016
Women In Steady Exercise Research (WISER) Sister: study design and methods.
    Contemporary clinical trials, 2015, Volume: 41

    Women at elevated risk for breast cancer are motivated to reduce their risk. Current approaches rely primarily on hormonal intervention. A preventive exercise intervention might address the same hormonal issues, yet have fewer serious side effects and less negative impact on quality of life as compared to prophylactic mastectomy. WISER Sister was a randomized controlled trial which examined effects of two doses of exercise training on endogenous sex hormone exposure, hormonally active breast tissue, and other breast cancer risk factors.. Subjects for this single site trial were recruited from across the U.S., in collaboration with organizations that serve women at elevated risk, via emails, flyers, and letters. Eligibility criteria included age ≥ 18, eumenorrheic, and at elevated risk for breast cancer (e.g. BRCA1 or BRCA2 mutation and/or ≥ 18% lifetime risk according to prediction models). A 1:1:1 randomization scheme was used to allocate participants into: control, low dose (150 min/week), or high dose (300 min/week) home based treadmill exercise. Participants provided first morning urine samples daily for two menstrual cycles at study beginning and end for calculation of endogenous hormone exposure. In addition, women completed breast dynamic contrast enhanced magnetic resonance imaging, a fasting blood draw, a treadmill exercise test, and surveys at baseline and follow-up.. WISER Sister randomized 139 women, 122 of whom completed the study. The overall drop-out rate was 12%. Findings will be useful in understanding the potential for exercise to assist with reducing risk for breast cancer among women at elevated risk.

    Topics: Adiponectin; Adult; Breast; Breast Neoplasms; Estrone; Exercise Therapy; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Heterozygote; Humans; Leptin; Magnetic Resonance Imaging; Mutation; Pregnanediol; Risk Reduction Behavior; Treatment Outcome

2015
Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32.
    Journal of the National Cancer Institute, 2015, Volume: 107, Issue:3

    Metformin may improve metabolic factors (insulin, glucose, leptin, highly sensitive C-reactive protein [hs-CRP]) associated with poor breast cancer outcomes. The NCIC Clinical Trials Group (NCIC CTG) MA.32 investigates effects of metformin vs placebo on invasive disease-free survival and other outcomes in early breast cancer. Maintaining blinding of investigators to outcomes, we conducted a planned, Data Safety Monitoring Committee-approved, analysis of the effect of metformin vs placebo on weight and metabolic factors at six months, including examination of interactions with baseline body mass index (BMI) and insulin, in the first 492 patients with paired blood samples.. Eligible nondiabetic subjects with T1-3, N0-3, M0 breast cancer who had completed surgery and (neo)adjuvant chemotherapy (if given) provided fasting plasma samples at random assignment and at six months. Glucose was measured locally; blood was aliquoted, frozen, and stored at -80°C. Paired plasma aliquots were analyzed for insulin, hs-CRP, and leptin. Spearman correlation coefficients were calculated and comparisons analyzed using Wilcoxon signed rank test. All statistical tests were two-sided.. Mean age was 52.1±9.5 years in the metformin group and 52.6 ± 9.8 years in the placebo group. Arms were balanced for estrogen/progesterone receptor, BMI, prior (neo)adjuvant chemotherapy, and stage. At six months, decreases in weight and blood variables were statistically significantly greater in the metformin arm (vs placebo) in univariate analyses: weight -3.0%, glucose -3.8%, insulin -11.1%, homeostasis model assessment -17.1%, leptin -20.2%, hs-CRP -6.7%; all P values were less than or equal to .03. There was no statistically significant interaction of change in these variables with baseline BMI or insulin.. Metformin statistically significantly improved weight, insulin, glucose, leptin, and CRP at six months. Effects did not vary by baseline BMI or fasting insulin.

    Topics: Adult; Aged; Blood Glucose; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Metformin; Middle Aged; Neoplasm Staging; North America; Research Design; Statistics, Nonparametric; Switzerland; United Kingdom

2015
Effects of a walking intervention using mobile technology and interactive voice response on serum adipokines among postmenopausal women at increased breast cancer risk.
    Hormones & cancer, 2014, Volume: 5, Issue:2

    Practical methods to reduce the risk of obesity-related breast cancer among high-risk subgroups are lacking. Few studies have investigated the effects of exercise on circulating adipokines, which have been shown to be associated with obesity and breast cancer. The aim of this study was to examine the effects of a walking intervention on serum adiponectin, leptin, and the adiponectin-to-leptin ratio (A/L). Seventy-one overweight and obese postmenopausal women at increased risk of developing breast cancer were stratified by BMI (25-30 kg/m(2) or >30 kg/m(2)) and randomized to a 12-week, two-arm walking intervention administered through interactive voice response (IVR) and mobile devices. The intervention arms were IVR + coach and IVR + no-coach condition. Pre-post changes in serum adiponectin, leptin, and the A/L ratio were examined using mixed regression models, with ratio estimates (and 95 % confidence intervals [CI]) corresponding to postintervention adipokine concentrations relative to preintervention concentrations. While postintervention effects included statistically significant improvements in anthropometric measures, the observed decreases in adiponectin and leptin (ratio = 0.86, 95 % CI 0.74-1.01, and ratio = 0.94, 95 % CI 0.87-1.01, respectively) and increase in A/L ratio = 1.09, 95 % CI 0.94-1.26) were not significant. Thus, these findings do not support significant effects of the walking intervention on circulating adipokines among overweight and obese postmenopausal women. Additional studies are essential to determine the most effective and practical lifestyle interventions that can promote beneficial modification of serum adipokine concentrations, which may prove useful for obesity-related breast cancer prevention.

    Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Cell Phone; Female; Health Promotion; Humans; Leptin; Middle Aged; Obesity; Overweight; Postmenopause; Risk Factors; Telemedicine; Time Factors; Treatment Outcome; Walking

2014
Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer.
    Cancer investigation, 2014, Volume: 32, Issue:4

    We conducted a presurgical trial to assess the tissue-related effects of metformin in overweight/obese breast cancer (BC) patients.. Metformin 1,500 mg daily was administered to 35 nondiabetics with stage 0-III BC, body mass index (BMI) ≥ 25 kg/m(2). The primary endpoint was tumor proliferation change (i.e., ki-67). Tumor proliferation change was compared to untreated historical controls, matched by age, BMI, and stage.. There was no reduction in ln(ki-67) after metformin (p = .98) or compared to controls (p = .47). There was a significant reduction in BMI, cholesterol, and leptin.. Despite no proliferation changes, we observed reductions in other relevant biomarkers.

    Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Cell Proliferation; Chemotherapy, Adjuvant; Cholesterol; Drug Administration Schedule; Female; Humans; Leptin; Metformin; Middle Aged; Neoplasm Staging; New York City; Obesity; Overweight; Time Factors; Treatment Outcome

2014
Association between prediagnostic biomarkers of inflammation and endothelial function and cancer risk: a nested case-control study.
    American journal of epidemiology, 2013, Jan-01, Volume: 177, Issue:1

    Experimental and prevalent case-control studies suggest an association between biomarkers of inflammation, endothelial function, and adiposity and cancer risk, but results from prospective studies have been limited. The authors' objective was to prospectively examine the relations between these biomarkers and cancer risk. A nested case-control study was designed within the Supplémentation en Vitamines et Minéraux Antioxydants (SU.VI.MAX) Study, a nationwide French cohort study, to include all first primary incident cancers diagnosed between 1994 and 2007 (n = 512). Cases were matched with randomly selected controls (n = 1,024) on sex, age (in 2-year strata), body mass index (weight (kg)/height (m)(2); <25 vs. ≥25), and SU.VI.MAX intervention group. Conditional logistic regression was used to study the associations between prediagnostic levels of high-sensitivity C-reactive protein (hs-CRP), adiponectin, leptin, soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1, soluble E-selectin, and monocyte chemoattractant protein 1 and cancer risk. All statistical tests were 2-sided. Plasma sICAM-1 level was positively associated with breast cancer risk (for quartile 4 vs. quartile 1, multivariate odds ratio (OR) = 1.86, 95% confidence interval (CI): 1.06, 3.26; P(trend) = 0.048). Plasma hs-CRP level was positively associated with prostate cancer risk (for quartile 4 vs. quartile 1, multivariate OR = 3.04, 95% CI: 1.28, 7.23; P(trend) = 0.03). These results suggest that prediagnostic hs-CRP and sICAM-1 levels are associated with increased prostate and breast cancer risk, respectively.

    Topics: Adiponectin; Adiposity; Adult; Biomarkers; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Cell Adhesion Molecules; Chemokine CCL2; Double-Blind Method; Endothelium; Female; Health Behavior; Humans; Inflammation; Leptin; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Risk Factors

2013
Prognostic effect of circulating adiponectin in a randomized 2 x 2 trial of low-dose tamoxifen and fenretinide in premenopausal women at risk for breast cancer.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2012, Jan-10, Volume: 30, Issue:2

    Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer.. We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period.. At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels.. Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.

    Topics: Adiponectin; Anticarcinogenic Agents; Breast Neoplasms; Double-Blind Method; Female; Fenretinide; Humans; Leptin; Middle Aged; Premenopause; Prognosis; Risk Factors; Tamoxifen

2012
Outcomes of a weight loss intervention among rural breast cancer survivors.
    Breast cancer research and treatment, 2012, Volume: 132, Issue:2

    Obese breast cancer survivors have increased risk of recurrence and death compared to their normal weight counterparts. Rural women have significantly higher obesity rates, thus weight control intervention may be a key strategy for prevention of breast cancer recurrence in this population. This one-arm treatment study examined the impact of a group-based weight control intervention delivered through conference call technology to obese breast cancer survivors living in remote rural locations. The intervention included a reduced calorie diet incorporating prepackaged entrees and shakes, physical activity gradually increased to 225 min/week of moderate intensity exercise, and weekly group phone sessions. Outcomes included anthropomorphic, diet, physical activity, serum biomarker, and quality of life changes. Ninety-one percent of participants (31 of 34) attended >75% of intervention sessions and completed post-treatment data collection visits. At 6 months, significant changes were observed for weight (-12.5 ± 5.8 kg, 13.9% of baseline weight), waist circumference (-9.4 ± 6.3 cm), daily energy intake (-349 ± 550 kcal/day), fruits, and vegetables (+3.7 ± 4.3 servings/day), percent kcal from fat (-12.6 ± 8.6%), physical activity (+1235 ± 832 kcal/week; all P values <0.001), as well as significant reductions in fasting insulin (16.7% reduction, P = 0.006), and leptin (37.1% reduction, P < 0.001). Significant improvements were also seen for quality of life domains including mood, body image, and sexuality. In conclusion, the intervention produced >10% weight loss as well as significant improvements across multiple endpoints. The group phone-based treatment delivery approach may help disseminate effective weight control intervention to hard-to-reach breast cancer survivors.

    Topics: Aged; Analysis of Variance; Biomarkers; Breast Neoplasms; Caloric Restriction; Exercise Therapy; Female; Group Processes; Humans; Insulin; Kansas; Leptin; Middle Aged; Obesity; Quality of Life; Remote Consultation; Rural Health Services; Surveys and Questionnaires; Survivors; Telephone; Time Factors; Treatment Outcome; Weight Loss

2012
25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.
    Breast cancer research and treatment, 2012, Volume: 133, Issue:3

    Observational studies suggest that host factors are associated with breast cancer risk. The influence of obesity, vitamin-D status, insulin resistance, inflammation, and elevated adipocytokines in women at high risk of breast cancer is unknown. The NSABP-P1 trial population was used for a nested case-control study. Cases were drawn from those who developed invasive breast cancer and controls selected from unaffected participants (≤4 per case) matched for age, race, 5 year Gail score, and geographic location of clinical center as a surrogate for latitude. Fasting serum banked at trial enrolment was assayed for 25-hydroxy vitamin-D (25OHD), insulin, leptin (adipocytokine), and C-reactive protein (CRP, marker of inflammation). Logistic regression was used to test for associations between study variables and the risk of invasive breast cancer. Two hundred and thirty-one cases were matched with 856 controls. Mean age was 54, and 49% were premenopausal. There were negative correlations for 25OHD with body mass index (BMI), insulin, CRP, and leptin. BMI ≥ 25 kg/m(2) was associated with higher breast cancer risk (odds ratio [OR] 1.45, p = 0.02) and tamoxifen treatment was associated with lower risk (OR = 0.44, p < 0.001). Suboptimal 25OHD (<72 nmol/l) did not influence breast cancer risk (OR = 1.06, p = 0.76). When evaluated as continuous variables, 25OHD, insulin, CRP, and leptin levels were not associated with breast cancer risk (all p > 0.34). In this high risk population, higher BMI was associated with a greater breast cancer risk. Serum levels of 25OHD, insulin, CRP, and leptin were not independent predictors of either breast cancer risk or tamoxifen benefit.

    Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Female; Humans; Insulin; Leptin; Middle Aged; Obesity; Odds Ratio; Risk; Tamoxifen; Vitamin D

2012
Effect of a low fat versus a low carbohydrate weight loss dietary intervention on biomarkers of long term survival in breast cancer patients ('CHOICE'): study protocol.
    BMC cancer, 2011, Jul-06, Volume: 11

    Weight loss in overweight or obese breast cancer patients is associated with an improved prognosis for long term survival. However, it is not clear whether the macronutrient composition of the chosen weight loss dietary plan imparts further prognostic benefit. A study protocol is presented for a dietary intervention to investigate the effects of weight loss dietary patterns that vary markedly in fat and carbohydrate contents on biomarkers of exposure to metabolic processes that may promote tumorigenesis and that are predictive of long term survival. The study will also determine how much weight must be lost for biomarkers to change in a favorable direction.. Approximately 370 overweight or obese postmenopausal breast cancer survivors (body mass index: 25.0 to 34.9 kg/m²) will be accrued and assigned to one of two weight loss intervention programs or a non-intervention control group. The dietary intervention is implemented in a free living population to test the two extremes of popular weight loss dietary patterns: a high carbohydrate, low fat diet versus a low carbohydrate, high fat diet. The effects of these dietary patterns on biomarkers for glucose homeostasis, chronic inflammation, cellular oxidation, and steroid sex hormone metabolism will be measured. Participants will attend 3 screening and dietary education visits, and 7 monthly one-on-one dietary counseling and clinical data measurement visits in addition to 5 group visits in the intervention arms. Participants in the control arm will attend two clinical data measurement visits at baseline and 6 months. The primary outcome is high sensitivity C-reactive protein. Secondary outcomes include interleukin-6, tumor necrosis factor-α, insulin-like growth factor-1 (IGF), IGF binding protein-3, 8-isoprostane-F2-alpha, estrone, estradiol, progesterone, sex hormone binding globulin, adiponectin, and leptin.. While clinical data indicate that excess weight for height is associated with poor prognosis for long term survival, little attention is paid to weight control in the clinical management of breast cancer. This study will provide information that can be used to answer important patient questions about the effects of dietary pattern and magnitude of weight loss on long term survival following breast cancer treatment.. CA125243.

    Topics: Adiponectin; Adipose Tissue; Algorithms; Analysis of Variance; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Diet, Reducing; Dietary Carbohydrates; Dietary Fats; Estrogens; Female; Glucose; Homeostasis; Humans; Interleukin-6; Leptin; Middle Aged; Obesity; Outcome Assessment, Health Care; Postmenopause; Reactive Oxygen Species; Survivors; Tumor Necrosis Factor-alpha; Weight Reduction Programs

2011
Impact of a mixed strength and endurance exercise intervention on levels of adiponectin, high molecular weight adiponectin and leptin in breast cancer survivors.
    Cancer causes & control : CCC, 2009, Volume: 20, Issue:8

    Evidence suggests that exercise affects breast cancer risk and outcomes, but little is known about the mechanisms through which this effect may be mediated. This study examines the impact of exercise upon levels of adiponectin, high molecular weight adiponectin (HMWA), and leptin in breast cancer survivors.. One hundred and one sedentary, overweight breast cancer survivors were randomized to a 16-week exercise intervention or usual care control group. Anthropometric measurements were taken and fasting levels of adiponectin, HMWA and leptin were collected at baseline and 16 weeks.. Baseline and week-16 measurements were available for 81 patients. The exercise group experienced a significant decrease in hip measurements, with no change in weight or body composition. There were no significant changes in adiponectin, HMWA, or leptin in either group. Modeling analyses demonstrated a significant inverse relationship between changes in leptin and adiponectin, but no relationship between changes in BMI, waist or hip circumference, or body fat percentage and change in leptin or adiponectin.. This study did not demonstrate a significant change in adipocytokine levels in breast cancer survivors participating in an exercise intervention, suggesting that further work is needed to explore the mechanisms through which exercise may impact breast cancer.

    Topics: Adiponectin; Adult; Breast Neoplasms; Exercise; Exercise Therapy; Female; Humans; Leptin; Middle Aged; Molecular Weight; Physical Endurance; Physical Fitness; Resistance Training; Survivors

2009
Effect of fenretinide and low-dose tamoxifen on insulin sensitivity in premenopausal women at high risk for breast cancer.
    Cancer research, 2008, Nov-15, Volume: 68, Issue:22

    The prevalence of metabolic syndrome is increasing along with breast cancer incidence worldwide. Because fenretinide improves insulin action and glucose tolerance in insulin-resistant obese mice and because tamoxifen has shown to regulate several markers involved in metabolic syndrome, we sought to investigate the effect of fenretinide or tamoxifen at low dose on features linked to insulin resistance in premenopausal women at risk for breast cancer. We randomized 235 women to low-dose tamoxifen (5 mg/daily), fenretinide (200 mg/daily), or their combination or placebo for 2 years. We used the homeostasis model assessment (HOMA; fasting insulin x glucose/22.5) to estimate insulin sensitivity. Women were considered to improve insulin sensitivity when they shifted from a HOMA >/=2.8 to <2.8. There was no effect of fenretinide or tamoxifen on HOMA overall, but overweight women (body mass index, >or=25 kg/m(2)) had a 7-fold greater probability to normalize HOMA after 2 years of fenretinide treatment [odds ratio (OR), 7.0; 95% confidence interval (95% CI), 1.2-40.5], with 25% of women improving their insulin sensitivity, whereas tamoxifen decreased insulin sensitivity by almost 7 times compared with subjects not taking tamoxifen (OR, 0.15; 95% CI, 0.03-0.88). In this group only, 5% improved their insulin sensitivity. Interestingly, women with intraepithelial or microinvasive neoplasia had higher HOMA (3.0) than unaffected subjects (2.8; P = 0.07). Fenretinide can positively balance the metabolic profile in overweight premenopausal women and this may favorably affect breast cancer risk. Furthermore, features of the metabolic syndrome should be taken into consideration before proposing tamoxifen for breast cancer prevention. The clinical implications of these results require further investigations.

    Topics: Antineoplastic Agents; Body Mass Index; Breast Neoplasms; Cholesterol, HDL; Double-Blind Method; Female; Fenretinide; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Premenopause; Retinol-Binding Proteins, Plasma; Tamoxifen

2008
Improvement of metabolism among obese breast cancer survivors in differing weight loss regimens.
    Obesity research, 2004, Volume: 12, Issue:2

    To compare the efficacy of different weight loss regimens on body weight loss and metabolic improvement in breast cancer survivors.. Forty-eight obese breast cancer survivors were randomly divided into four groups and were followed for 1 year: 1) the Control group (subjects did not receive specific nutrition counseling); 2) the Weight Watchers group (subjects were given free coupons to attend weekly Weight Watchers meetings); 3) the Individualized group (a registered dietitian provided one-on-one nutritional counseling); and 4) the Comprehensive group (subjects received individualized dietary counseling and free coupons for the weekly Weight Watchers meetings). At baseline and 3-, 6-, and 12-month data collection visits, a fasting blood sample was obtained for assays. A three-day dietary record was kept during the week before these visits and dietary intake was analyzed.. Subjects in the three intervention groups lost weight (Control: 1.1 +/- 1.7 kg; Weight Watchers: -2.7 +/- 2.1 kg; Individualized: -8.0 +/- 1.9 kg; Comprehensive: -9.5 +/- 2.7 kg) and percentage body fat, but only the Individualized and Comprehensive groups had significant losses. Subjects in the Comprehensive group showed the most improvement in cholesterol levels and had reductions in blood leptin levels.. Because insulin resistance and high blood leptin levels are associated with breast cancer, losing weight to improve these parameters may reduce the risk of recurrence. Only subjects in the Comprehensive group showed significant reductions in body weight and fat, energy intake, and leptin levels. For breast cancer survivors, different weight loss strategies should be considered to assist them in losing weight.

    Topics: Adolescent; Adult; Aged; Breast Neoplasms; Counseling; Diet, Reducing; Dietetics; Female; Humans; Insulin; Leptin; Middle Aged; Neoplasm Recurrence, Local; Obesity; Self-Help Groups; Survivors; Weight Loss

2004
Effect of raloxifene on insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin in premenopausal women at high risk for developing breast cancer.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2003, Volume: 12, Issue:12

    Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70 degrees C until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (CI), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation.

    Topics: Administration, Oral; Adult; Age Factors; Biomarkers, Tumor; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Middle Aged; Pilot Projects; Premenopause; Probability; Raloxifene Hydrochloride; Risk Assessment; Sensitivity and Specificity; Statistics, Nonparametric

2003
Antiestrogenic tamoxifen and toremifene increase serum leptin levels in postmenopausal breast cancer patients.
    Maturitas, 2000, May-29, Volume: 35, Issue:2

    Because estrogens stimulate the synthesis and release of leptin in the adipocytes, the effect of antiestrogens on the circulating leptin levels were studied.. Thirty postmenopausal patients with breast cancer were randomized to start either with tamoxifen (20 mg/day, n=15) or toremifene (40 mg/day, n=15), and the patients were examined and serum leptin concentrations measured before the study and at 6 and 12 months.. The baseline leptin concentrations ranged from 4.4 to 60.0 microg/l (15.3+/-13.1 microg/l, mean+/-S.D.), and it correlated positively with the body mass index (BMI) of the subjects (r=0.73, P=0.0001). Taking as a whole the antiestrogen regimen was associated with elevated leptin levels at 6 months (19.5+/-13.8 microg/l, P=0.0001) but no excess increase in leptin levels were seen at 12 months (20.9+/-13.5 microg/l, NS). Subgroup analysis showed no difference between the effects of tamoxifen or toremifene on leptin. BMI increased in 21 women (from 26.2+/-4.3 to 27.3+/-4.8 kg/m2, P=0.0001) at 6 months, but not after that; in nine women BMI did not change. There was no significant correlation between the change in leptin levels and the change in BMI in either group implying that antiestrogens may specifically stimulate leptin production.. Antiestrogens may stimulate the synthesis and release of leptin in the adipocytes. This effect of antiestrogens resembles the effect of estrogen and consequently stimulation of leptin production can be added to the estrogenic effects of antiestrogens.

    Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Estrogen Receptor Modulators; Female; Humans; Leptin; Middle Aged; Postmenopause; Tamoxifen; Toremifene

2000

Other Studies

275 other study(ies) available for leptin and Breast-Neoplasms

ArticleYear
Adipocytes secretome from normal and tumor breast favor breast cancer invasion by metabolic reprogramming.
    Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 2023, Volume: 25, Issue:5

    Adipose tissue is a major component of breast stroma. This study focused on delineating the effects of adipose stem cells (ASCs) derived from breast of healthy women and cancer patients with normal or tumor breast cells.. The ASCs were induced to differentiate into adipocytes, and the subsequent adipocyte conditioned media (ACM) were evaluated for their fatty acid profile, adipokine secretion and influence on proliferation, migration and invasion on tumoral (MCF-7 and SUM159) and normal (HMEC) human breast cell lines.. An enrichment of arachidonic acid was observed in ACM from tumor tissues. Adipose tissues from tumor free secrete twice as much leptin than those from proximal or distal to the tumor. All ACMs display proliferative activity and favor invasiveness of SUM159 cells compared to MCF-7 and HMEC. All ACMs induced lipid droplets accumulation in MCF-7 cells and increased CD36 expression in tumor cells.. We conclude that among secreted factors analyzed, only arachidonic acid and leptin levels did discriminate ASCs from tumor-bearing and tumor-free breasts emphasizing the importance that other cell types could contribute to the adipose tissue secretome in a tumor context.

    Topics: Adipocytes; Adipose Tissue; Arachidonic Acid; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Culture Media, Conditioned; Female; Humans; Leptin; MCF-7 Cells; Secretome

2023
Effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women: a pilot study.
    European journal of clinical pharmacology, 2023, Volume: 79, Issue:2

    Metformin may provide a therapeutic benefit in different types of malignancy.. We aimed at evaluating the effect of metformin as an adjuvant therapy to letrozole on estradiol and other biomarkers involved in the pathogenesis of breast cancer in overweight and obese postmenopausal women.. Seventy-five postmenopausal stages II-III breast cancer female patients were assessed for eligibility in an open-labeled parallel pilot study. Forty-five patients met the inclusion criteria and were assigned into three arms: the lean arm (n = 15) women who received letrozole 2.5 mg/day, the control arm (n = 15) overweight/obese women who received letrozole 2.5 mg/day, and the metformin arm (n = 15) overweight/obese women who received letrozole 2.5 mg/day plus metformin (2000 ± 500 mg/day). The intervention duration was 6 months. Blood samples were obtained at baseline and 6 months after intervention for the measurement of serum estradiol, leptin, osteocalcin levels, fasting blood glucose concentration, and serum insulin.. After the intervention and as compared to the control arm, the metformin arm showed a significantly lower ratio to the baseline (significant reduction) for estradiol (p = 0.0433), leptin (p < 0.0001), fasting blood glucose (p = 0.0128), insulin (p = 0.0360), osteocalcin serum levels (p < 0.0001), and the homeostatic model assessment of insulin resistance "HOMA-IR" value (p = 0.0145). There was a non-significant variation in the lactate ratio to the baseline among the three study arms (p = 0.5298).. Metformin may exert anti-cancer activity by decreasing the circulating estradiol, leptin, and insulin. Metformin might represent a safe and promising adjuvant therapy to letrozole in overweight/obese postmenopausal women with breast cancer.. ClinicalTrials.gov Identifier: NCT05053841/Registered September 23, 2021 - Retrospectively.

    Topics: Biomarkers; Blood Glucose; Breast Neoplasms; Estradiol; Female; Humans; Insulin; Leptin; Letrozole; Metformin; Obesity; Osteocalcin; Overweight; Pilot Projects; Postmenopause; Retrospective Studies

2023
Obesity and metabolic dysfunction correlate with background parenchymal enhancement in premenopausal women.
    Obesity (Silver Spring, Md.), 2023, Volume: 31, Issue:2

    This study tested the hypothesis that obesity and metabolic abnormalities correlate with background parenchymal enhancement (BPE), the volume and intensity of enhancing fibroglandular breast tissue on dynamic contrast-enhanced magnetic resonance imaging.. Participants included 59 premenopausal women at high risk of breast cancer. Obesity was defined as BMI ≥ 30 kg/m. BMI was positively correlated with BPE (r = 0.69; p < 0.001); participants with obesity had higher BPE than those without obesity (404.9 ± 189.6 vs. 261.8 ± 143.8 cm. In premenopausal women at high risk of breast cancer, increased BPE is associated with obesity, insulin resistance, leptin, and adiponectin.

    Topics: Adiponectin; Breast Neoplasms; Female; Humans; Inflammation; Insulin Resistance; Leptin; Lipids; Obesity

2023
Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in
    Science translational medicine, 2023, 02-22, Volume: 15, Issue:684

    Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in

    Topics: Animals; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; DNA Damage; Epithelium; Estrogens; Female; Germ-Line Mutation; Humans; Leptin; Mammary Glands, Human; Mice; Mutation; Obesity; Phosphatidylinositol 3-Kinases; Tumor Microenvironment

2023
Linking Physical Activity to Breast Cancer Risk via Inflammation, Part 1: The Effect of Physical Activity on Inflammation.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023, 05-01, Volume: 32, Issue:5

    The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = -0.27, 95% confidence interval (CI) = -0.62 to 0.08), tumor necrosis factor alpha (TNFα, SMD = -0.63, 95% CI = -1.04 to -0.22), interleukin-6 (IL6, SMD = -0.55, 95% CI = -0.97 to -0.13) and leptin (SMD = -0.50, 95% CI = -1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFα and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = -0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity-inflammation-breast cancer pathway.

    Topics: Adult; Breast Neoplasms; C-Reactive Protein; Exercise; Female; Humans; Inflammation; Interleukin-6; Leptin; Quality of Life; Tumor Necrosis Factor-alpha

2023
Leptin and leptin receptor expression as biomarkers for breast cancer: a retrospective study.
    BMC cancer, 2023, Mar-20, Volume: 23, Issue:1

    Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary.. To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC.. Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan-Meier curve was generated to test survival time.. The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival (all P > 0.05).. High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival.

    Topics: Biomarkers; Breast Neoplasms; Carcinoma; Female; Humans; Leptin; Polymorphism, Single Nucleotide; Receptors, Leptin; Retrospective Studies

2023
Maternal obesity driven changes in collagen linearity of breast extracellular matrix induces invasive mammary epithelial cell phenotype.
    Biomaterials, 2023, Volume: 297

    Obesity has been linked with numerous health issues as well as an increased risk of breast cancer. Although effects of direct obesity in patient outcomes is widely studied, effects of exposure to obesity-related systemic influences in utero have been overlooked. In this study, we investigated the effect of multigenerational obesity on epithelial cell migration and invasion using decellularized breast tissues explanted from normal female mouse pups from a diet induced multigenerational obesity mouse model. We first studied the effect of multigenerational diet on the mechanical properties, adipocyte size, and collagen structure of these mouse breast tissues, and then, examined the migration and invasion behavior of normal (KTB-21) and cancerous (MDA-MB-231) human mammary epithelial cells on the decellularized matrices from each diet group. Breast tissues of mice whose dams had been fed with high-fat diet exhibited larger adipocytes and thicker and curvier collagen fibers, but only slightly elevated elastic modulus and inflammatory cytokine levels. MDA-MB-231 cancer cell motility and invasion were significantly greater on the decellularized matrices from mice whose dams were fed with high-fat diet. A similar trend was observed with normal KTB-21 cells. Our results showed that the collagen curvature was the dominating factor on this enhanced motility and stretching the matrices to equalize the collagen fiber linearity of the matrices ameliorated the observed increase in cell migration and invasion in the mice that were exposed to a high-fat diet in utero. Previous studies indicated an increase in serum leptin concentration for those children born to an obese mother. We generated extracellular matrices using primary fibroblasts exposed to various concentrations of leptin. This produced curvier ECM and increased breast cancer cell motility for cells seeded on the decellularized ECM generated with increasing leptin concentration. Our study shows that exposure to obesity in utero is influential in determining the extracellular matrix structure, and that the resultant change in collagen curvature is a critical factor in regulating the migration and invasion of breast cancer cells.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Child; Collagen; Epithelial Cells; Extracellular Matrix; Female; Humans; Leptin; Mice; Obesity; Obesity, Maternal; Phenotype; Pregnancy

2023
Increases in BMI contribute to worsening inflammatory biomarkers related to breast cancer risk in women: a longitudinal study.
    Breast cancer research and treatment, 2023, Volume: 202, Issue:1

    Inflammatory adipokines and cytokines play a pivotal role in linking obesity and breast cancer (BC) risk in women. We investigated the longitudinal associations between BMI change and trajectories of inflammatory biomarkers related to BC risk.. A longitudinal study was conducted among 442 Chinese women with 3-year repeated measures from 2019 to 2021. Plasma circulating inflammatory biomarkers related to BC risk, including adiponectin (ADP), resistin (RETN), soluble leptin receptor (sOB-R), insulin-like growth factor-binding protein-3 (IGFBP-3), and C-reactive protein (CRP), were examined annually. Linear mixed-effect models (LMM) were applied to investigate associations of time-varying BMI with trajectories of biomarkers. We additionally examined the modification effect of baseline BMI groups, menopausal status, and metabolic syndrome.. BMI was associated with increased levels of RETN, CRP, sOB-R, and decreased levels of ADP at baseline. An increasing BMI rate was significantly associated with an average 3-year increase in RETN (β = 0.019, 95% CI 0.004 to 0.034) and sOB-R (β = 0.022, 95% CI 0.009 to 0.035), as well as a decrease in ADP (β =  - 0.006, 95% CI  - 0.012 to 0.001). These associations persisted across different baseline BMI groups. An increasing BMI rate was significantly associated with an average 3-year increase in CRP levels among normal weight (β = 0.045, 95% CI 0.001 to 0.088) and overweight (β = 0.060, 95% CI 0.014 to 0.107) women. As BMI increased over time, a more remarkable decrease in ADP was observed among women with metabolic syndrome (β =  - 0.016, 95% CI - 0.029 to - 0.004) than those without metabolic syndrome at baseline.. A higher increase rate of BMI was associated with poorer trajectories of inflammatory biomarkers related to BC risk. Recommendations for BMI reduction may benefit BC prevention in women, particularly for those with metabolic syndrome.

    Topics: Adiponectin; Biomarkers; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Female; Humans; Leptin; Longitudinal Studies; Metabolic Syndrome

2023
Acupuncture improves immunity and fatigue after chemotherapy in breast cancer patients by inhibiting the Leptin/AMPK signaling pathway.
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2023, Aug-05, Volume: 31, Issue:9

    Acupuncture has become a popular complementary treatment in oncology. This study is based on RNA-Seq transcriptome sequencing technology to investigate the molecular mechanisms underlying the effect of acupuncture-mediated regulation of the Leptin/AMPK signaling pathway on mitochondrial dysfunction-induced fatigue in breast cancer patients after chemotherapy.. Peripheral blood samples from 10 patients with post-operative chemotherapy for breast cancer were selected for transcriptome sequencing to screen the key molecular pathways involved in fatigue after chemotherapy in breast cancer patients. Besides, peripheral blood samples were collected from 138 post-operative chemotherapy patients with breast cancer to study the composite fatigue and quality of life scores. Flow cytometry was used to detect T lymphocyte subsets in peripheral blood-specific immune cells. In addition, a blood cell analyzer was used to measure peripheral blood leukocyte counts, and MSP-PCR was used to detect mitochondrial DNA mutations in peripheral blood leukocytes.. Transcriptome bioinformatics analysis screened 147 up-regulated mRNAs and 160 down-regulated mRNAs. Leptin protein was confirmed as the key factor. Leptin was significantly higher in the peripheral blood of breast cancer patients who developed fatigue after chemotherapy. Acupuncture treatment effectively improved post-chemotherapy fatigue and immune status in breast cancer patients, suppressed the expression of Leptin/AMPK signaling pathway-related factor and leukocyte counts, and significantly reduced the rate of mitochondrial DNA mutations in peripheral blood leukocytes.. The Leptin/AMPK signaling pathway may be the key molecular pathway affecting the occurrence of fatigue after chemotherapy in breast cancer patients. Leptin may improve post-chemotherapy fatigue in breast cancer patients by activating AMPK phosphorylation and alleviating mitochondrial functional impairment.

    Topics: Acupuncture Therapy; AMP-Activated Protein Kinases; Breast Neoplasms; DNA, Mitochondrial; Fatigue; Female; Humans; Leptin; Quality of Life; Signal Transduction

2023
WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity.
    Nutrients, 2023, Aug-04, Volume: 15, Issue:15

    Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors (

    Topics: Adipokines; Adiponectin; Breast Neoplasms; Cancer Survivors; Female; Humans; Leptin; Neoplasm Recurrence, Local; Obesity; Overweight; Survivors; Weight Loss

2023
Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C-reactive protein, fasting insulin, and estradiol.
    Cancer medicine, 2022, Volume: 11, Issue:4

    Mechanisms underlying the adiposity-cancer relationship are incompletely understood. We quantified the mediating roles of C-reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)-positive breast, endometrial, and colorectal cancer risk in postmenopausal women.. We used a case-cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case-control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis.. For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5-<25 kg/m. Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity-associated cancer risk in postmenopausal women.

    Topics: Adiposity; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Cohort Studies; Colorectal Neoplasms; Endometrial Neoplasms; Estradiol; Fasting; Female; Humans; Insulin; Leptin; Obesity; Postmenopause; Risk Factors

2022
Association of Leptin Receptor Q223R Gene Polymorphism and Breast Cancer Patients: A Case Control Study.
    Asian Pacific journal of cancer prevention : APJCP, 2022, Jan-01, Volume: 23, Issue:1

    Leptin is a hormone secreted from adipocytes that regulates metabolism and energy homeostasis through the leptin receptor (LEPR). The aim of this study was to investigate the association of leptin receptor gene Q223R gene polymorphism, and plasma leptin level among obese breast cancer females.. The study enrolled 160 breast cancer patients and 160 healthy control females. LEPR Q223R polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum leptin was determined using enzyme-linked immunosorbent assay human leptin kit.  Immunohistochemical tests from paraffin blocks were carried out for estrogen and progesterone staging using the precise antibodies.. An association was found between LEPR gene Q223R gene polymorphism among obese breast cancer females. Statistical difference was found between GG (60.6%) Arg/Arg genotype (OR=2.986; 95%CI=1.540 to 5.789; p= 0.001) compared to AA (33.1%) Gln/Gln genotype. GG Q223R LEPR polymorphism showed statistically significant difference among obese breast cancer patients (BMI more than 25) compared to control (P < 0.0001). GG genotype of Q223R LEPR polymorphism showed statistically significant increased leptin level (p-value =0.0001) among obese patients (mean± SD; 23.39±4.32) compared to control (17.83±5.67).. Q223R LEPR polymorphism GG genotype was associated with increased leptin profile among obese breast cancer females.

    Topics: Breast Neoplasms; Case-Control Studies; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Restriction Fragment Length; Receptors, Leptin

2022
Chronic Leptin Treatment Induces Epithelial-Mesenchymal Transition in MCF10A Mammary Epithelial Cells.
    Journal of mammary gland biology and neoplasia, 2022, Volume: 27, Issue:1

    Leptin is a cytokine-like hormone that functions as a link between obesity and breast cancer (BC). Leptin treatment induces Epithelial to Mesenchymal Transition (EMT) in BC cell lines. In non-tumoral breast epithelial MCF10A cells, acute leptin treatment induces partial EMT. However, the effect of chronic leptin treatment on EMT in non-tumorigenic breast cells has not been fully explored. This study aimed to evaluate the effect of chronic leptin treatment on the induction of EMT in MCF10A cells. We found that chronic leptin treatment induces a switch from an epithelial to a mesenchymal morphology, partial loss of E-cadherin and gain of vimentin expression. Immunolocalization experiments showed a partial loss of E-cadherin at cell junctions and increased cytoplasmic localization of vimentin in leptin-treated cells. Moreover, chronic leptin treatment increased collective cell migration and invasion. Furthermore, when cultured in non-adherent conditions leptin treated cells exhibited reduced cell aggregation, increased survival, and decreased apoptosis, which correlates with increased FAK and AKT phosphorylation. Finally, bioinformatic analysis in two publicly available RNAseq datasets from normal breast tissue shows that high levels of leptin mRNA correlate positively with the expression of mesenchymal markers, and negatively with epithelial markers. Thus, our results demonstrate that chronic leptin treatment induces EMT in non-tumorigenic MCF10A cells and suggest that high leptin expression in normal breast tissue may induce EMT and contribute to increased risk of breast cancer.

    Topics: Breast Neoplasms; Cadherins; Cell Line; Cell Line, Tumor; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; Vimentin

2022
Correspondence on Leptin Receptor Q223R Gene Polymorphism and Breast Cancer.
    Asian Pacific journal of cancer prevention : APJCP, 2022, 02-01, Volume: 23, Issue:2

    Topics: Breast Neoplasms; Female; Humans; Leptin; Polymorphism, Genetic; Receptors, Leptin

2022
Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort.
    BMC medicine, 2022, 04-18, Volume: 20, Issue:1

    Inflammation has been hypothesized to play a role in the development and progression of breast cancer and might differently impact breast cancer risk among pre and postmenopausal women. We performed a nested case-control study to examine whether pre-diagnostic circulating concentrations of adiponectin, leptin, c-reactive protein (CRP), tumour necrosis factor-α, interferon-γ and 6 interleukins were associated with breast cancer risk, overall and by menopausal status.. Pre-diagnostic levels of inflammatory biomarkers were measured in plasma from 1558 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used conditional logistic regression to estimate the odds ratios (ORs) of breast cancer at blood collection, per one standard deviation increase in biomarker concentration.. Cases were diagnosed at a mean age of 61.4 years on average 8.6 years after blood collection. No statistically significant association was observed between inflammatory markers and breast cancer risk overall. In premenopausal women, borderline significant inverse associations were observed for leptin, leptin-to-adiponectin ratio and CRP [OR= 0.89 (0.77-1.03), OR= 0.88 (0.76-1.01) and OR= 0.87 (0.75-1.01), respectively] while positive associations were observed among postmenopausal women [OR= 1.16 (1.05-1.29), OR= 1.11 (1.01-1.23), OR= 1.10 (0.99-1.22), respectively]. Adjustment for BMI strengthened the estimates in premenopausal women [leptin: OR = 0.83 (0.68-1.00), leptin-to-adiponectin ratio: OR = 0.80 (0.66-0.97), CRP: OR = 0.85 (0.72-1.00)] but attenuated the estimates in postmenopausal women [leptin: OR = 1.09 (0.96-1.24), leptin-to-adiponectin ratio: OR = 1.02 (0.89-1.16), CRP: OR = 1.04 (0.92-1.16)].. Associations between CRP, leptin and leptin-to-adiponectin ratio with breast cancer risk may represent the dual effect of obesity by menopausal status although this deserves further investigation.

    Topics: Adipokines; Adiponectin; Biomarkers; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Female; Humans; Leptin; Middle Aged; Prospective Studies; Risk Factors

2022
Differential Expression of the Genes Coding for Adipokines and Epithelial Cell Polarity Components in Women With Low and High Mammographic Density.
    Clinical breast cancer, 2022, Volume: 22, Issue:7

    Women with extensive mammographic density (MD) are more likely to develop breast cancer than women with low MD because of a high epithelial component associated with a high proportion of stromal cells. To elucidate the biological association between high MD and risk of breast cancer, we compared the expression of a panel of genes coding for leptin, adiponectin, and some component of cell polarity and adherens junction complexes in dense and non-dense breast tissue.. We interrogated a public dataset composed by 120 specimens of normal breast tissue with MD evaluation. The differential expression of the selected genes in the 2 MD subgroups was assessed by the Wilcoxon test, whereas Kruskal-Wallis test evaluated the differential expression of single genes in the fatty, epithelium, or nonfatty compartment. Spearman's correlation measured the relationship among genes in the subset with the highest epithelium proportion.. In high MD, the expression level of PARD6B, CRB3, PATJ, LLGL2, CDH1, and MARVELD2 significantly lowered in tissues with the highest epithelium proportion, whereas, in low MD, the expression level of the genes increased with the increasing of the epithelium proportion. In the low MD subgroup, LEP correlated negatively with PRKCZ and DLG3, whereas, in high MD, such correlation was not observed.. The expression of the genes governing cell polarity establishment and cell-cell adhesion assembly differed significantly in the epithelial component of dense and non-dense breasts. The correlation pattern between LEP and PRKCZ or DLG3 agrees with the role of leptin in cell polarity disruption.

    Topics: Adipokines; Adiponectin; Breast; Breast Density; Breast Neoplasms; Cell Polarity; Epithelial Cells; Female; Humans; Leptin; Mammography; MARVEL Domain Containing 2 Protein; Risk Factors

2022
Inflammatory biomarkers and risk of breast cancer among young women in Latin America: a case-control study.
    BMC cancer, 2022, Aug-11, Volume: 22, Issue:1

    Breast cancer incidence is increasing rapidly in Latin America, with a higher proportion of cases among young women than in developed countries. Studies have linked inflammation to breast cancer development, but data is limited in premenopausal women, especially in Latin America.. We investigated the associations between serum biomarkers of chronic inflammation (interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), leptin, adiponectin) and risk of premenopausal breast cancer among 453 cases and 453 matched, population-based controls from Chile, Colombia, Costa Rica, and Mexico. Odds ratios (OR) were estimated using conditional logistic regression models. Analyses were stratified by size and hormonal receptor status of the tumors.. IL-6 (OR. The results of this study support the implication of chronic inflammation in breast cancer risk in young women in Latin America. Largest studies of prospective design are needed to confirm these findings in premenopausal women.

    Topics: Biomarkers; Breast Neoplasms; Case-Control Studies; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Latin America; Leptin; Risk Factors; Tumor Necrosis Factor-alpha

2022
Sleep quality traits correlate with inflammatory markers in the breast tissue of women.
    Cytokine, 2022, Volume: 160

    Several mechanisms have been posited to play a role in the sleep and breast cancer association, including alterations in immune function, but evidence remains inconclusive. A closer look at how sleep quality traits affect the breast microenvironment may provide clues for molecular mechanisms underlying the link between sleep and breast cancer. We examined the association between sleep quality traits (sleep duration, sleep aids, and insomnia) and tissue-based protein levels and gene expression of several inflammatory markers associated with breast cancer.. Breast tissues (normal n = 165 and adipose n = 74) were surgically obtained from women diagnosed with breast cancer. Protein levels by immunohistochemistry were determined using the quickscore method for 11 inflammatory markers in the normal epithelial breast tissue (interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), cyclooxygenase-2 (COX-2), leptin, serum amyloid A1 (SAA1), lactoferrin, transforming growth factor-beta (TGF-β), and signal transducer and activator of transcription 3 markers (STAT3). Relative quantification of 4 genes (COX-2, IL-6, TNF-α and LEP) in the adipose breast tissue was carried out using qPCR. Patient characteristics and sleep traits (average sleep duration per night, taking sleeping aids in the past year, and the average number of insomnia episodes per month) were determined by telephone interview. Associations were tested using Spearman's rank correlation (r. TGF-β and CRP levels in normal epithelial breast tissue were positively correlated with sleep aids (ar. Our findings indicate that sleep duration, sleep aids, and insomnia may differently affect women's breast tissues depending on menopausal status. From a public health perspective, these results warrant further validation in larger studies. Since sleep is a modifiable factor, it may be an interesting approach for breast cancer prevention.

    Topics: Biomarkers; Breast Neoplasms; C-Reactive Protein; Cyclooxygenase 2; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Lactoferrin; Leptin; Sleep Initiation and Maintenance Disorders; Sleep Quality; STAT3 Transcription Factor; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Necrosis Factor-alpha

2022
Evaluation of Circulating MicroRNAs and Adipokines in Breast Cancer Survivors with Arm Lymphedema.
    International journal of molecular sciences, 2022, Sep-26, Volume: 23, Issue:19

    Breast cancer-related lymphedema (BCRL) is a form of secondary lymphedema that is characterized by abnormal swelling of one or both arms due to the accumulation of lymph fluid in the interstitial tissue spaces, resulting from obstruction of the lymphatic vessels due to surgery insults, radiotherapy, or chemotherapy. Due to the multifactorial nature of this condition, the pathogenesis of secondary lymphedema remains unclear and the search for molecular factors associated with the condition is ongoing. This study aimed to identify serum microRNAs and adipokines associated with BCRL. Blood was collected from 113 breast cancer survivors and processed to obtain serum for small RNA-sequencing (BCRL vs. non-BCRL, n = 7 per group). MicroRNAs that were differentially expressed (fold change >1.5, p < 0.05) between lymphedema cases and those without lymphedema were further quantified in a validation cohort through quantitative reverse transcription PCR (BCRL n = 16, non-BCRL, n = 83). Leptin and adiponectin levels were measured in a combined cohort (BCRL n = 23, non-BCRL n = 90) using enzyme-linked immunosorbent assays. Two of the most significantly upregulated microRNAs, miR-199a-3p and miR-151a-3p, were strongly correlated with the onset of lymphedema and diabetes mellitus in the BCRL group. Leptin levels were higher in the BCRL cohort compared to the non-BCRL cohort (p < 0.05). A metabolic syndrome biomarker, the adiponectin/leptin ratio, was found to be lower in the BCRL group than in the non-BCRL group (median: 0.28 vs. 0.41, p < 0.05). Extensive studies on the mechanisms of the identified microRNAs and association of leptin with arm lymphedema may provide new insights on the potential biomarkers for lymphedema that should be followed up in a prospective cohort study.

    Topics: Adipokines; Adiponectin; Arm; Breast Neoplasms; Cancer Survivors; Circulating MicroRNA; Female; Humans; Leptin; Lymph Node Excision; Lymphedema; Prospective Studies

2022
Proteomic Profiling of Extracellular Vesicles Released by Leptin-Treated Breast Cancer Cells: A Potential Role in Cancer Metabolism.
    International journal of molecular sciences, 2022, Oct-26, Volume: 23, Issue:21

    Tumor extracellular vesicles (EVs), as endocytic vesicles able to transport nucleic acids, proteins, and metabolites in recipient cells, have been recognized fundamental mediators of cell-to-cell communication in breast cancer. The biogenesis and release of EVs are highly regulated processes and both the quantity of EVs and their molecular cargo might reflect the metabolic state of the producing cells. We recently demonstrated that the adipokine leptin, whose circulating levels correlate with adipose tissue expansion, is an inducer of EV release from breast cancer cells. Here, we show a specific proteomic signature of EVs released by MCF-7 breast cancer cells grown in the presence of leptin (Lep-EVs), in attempt to find additional molecular effectors linking obesity to breast cancer biology. An analysis of the proteomic profile of Lep-EVs by LC-MS/MS revealed a significant enrichment in biological processes, molecular functions, and cellular components mainly related to mitochondrial machineries and activity, compared to protein content of EVs from untreated breast cancer cells. Metabolic investigations, carried out to assess the autocrine effects of these vesicles on breast cancer cells, revealed that Lep-EVs were able to increase ATP levels in breast cancer cells. This result is associated with increased mitochondrial respiration evaluated by Seahorse analyzer, supporting the concept that Lep-EVs can modulate MCF-7 breast cancer cell oxidative metabolism. Moreover, taking into account the relevance of tumor immune cell crosstalk in the tumor microenvironment (TME), we analyzed the impact of these vesicles on macrophage polarization, the most abundant immune component in the breast TME. We found that tumor-derived Lep-EVs sustain the polarization of M0 macrophages, derived from the human THP-1 monocytic cells, into M2-like tumor-associated macrophages, in terms of metabolic features, phagocytic activity, and increased expression of CD206-positive population. Overall, our results indicate that leptin by inducing the release of EV-enriched in mitochondrial proteins may control the metabolism of MCF-7 breast cancer cells as well as that of macrophages. Characterization of tumor-derived EV protein cargo in an obesity-associated milieu, such as in the presence of elevated leptin levels, might allow identifying unique features and specific metabolic mechanisms useful to develop novel therapeutic approaches for treatment of breast cancer, especially in obese pa

    Topics: Breast Neoplasms; Chromatography, Liquid; Extracellular Vesicles; Female; Humans; Leptin; Obesity; Proteomics; Tandem Mass Spectrometry; Tumor Microenvironment

2022
SERUM LEPTIN LEVEL IN BREAST CANCER.
    Acta clinica Croatica, 2022, Volume: 61, Issue:1

    Leptin is a polypeptide which is mostly produced in white fat tissue and is an important proinflammatory, proangiogenic, proinvasive and mitotic factor. There is ever more evidence suggesting the key role of leptin in the occurrence of breast cancer. The aim of the study was to investigate serum leptin levels in patients with benign breast tumors, as well as in various breast cancer phenotypes, taking into account leptin levels connected to menopausal status and body mass index (BMI). The study included 97 patients having their breast tumor surgically removed. Serum leptin level was determined by ELISA method in all study patients. Study results showed that significantly more women, regardless of having malignant or benign tumors, were postmenopausal and had a significantly higher level of leptin compared to the premenopausal group. The highest level of leptin was recorded in the group of postmenopausal obese women compared to other postmenopausal women but also compared to premenopausal women. According to BMI alone, obese women had a significantly higher level of leptin regardless of the type of tumor. The most significant differences in leptin levels observed through BMI were found in the Luminal B1 group. In conclusion, serum leptin level was shown to be a good diagnostic parameter suggesting a higher possibility of breast cancer development.

    Topics: Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Obesity; Postmenopause; Premenopause

2022
Leptin and its receptor are overexpressed in breast cancer tissue of postmenopausal Mexican-Mestizo women with obesity.
    Annals of diagnostic pathology, 2022, Volume: 60

    The aim of this study was to investigate the expression of leptin (LEP) and its receptor (LEPR) in breast cancer tissue of postmenopausal women with different body mass indexes (BMI), as well as the relationship of this expression with the rate of recurrence free survival (RFS). Leptin and LEPR expression, determined by immunohistochemistry, were studied in breast cancer tissues of 154 patients. Qualitative and semi-quantitative analysis of protein expression was performed by the H-Score method, through the ImageJ's IHC Profiler software. Kaplan-Meier survival analysis and log-rank statistic were used to estimate RFS differences. Protein expression of LEP, was significantly higher in women with overweight or with obesity, when compared to women with normal BMI (P = 0.032 and P = 0.013, respectively). We also observed a significantly higher expression of LEPR in breast tumor cells of women with obesity (58.8%), when compared to women with normal BMI (32.7%) (P = 0.007). Five-year survival rate, regarding LEPR expression, was 82.4% when positive and 94% when negative (P = 0.024). In the Cox proportional-hazards regression model, LEPR expression represented a risk factor for disease recurrence after adjustment for confounding factors (HR = 4.67; 95% CI: 1.13-19.31; P = 0.033). In conclusion, postmenopausal women with obesity and breast cancer present higher LEP and LEPR expression in breast tumors, when compared to women with normal BMI. Independently from BMI, women with tumors LEPR positive have worst RFS, when compared to women with tumors LEPR negative.

    Topics: Breast Neoplasms; Female; Humans; Leptin; Neoplasm Recurrence, Local; Obesity; Postmenopause; Receptors, Leptin

2022
'Energy-Dense, High-SFA and Low-Fiber' Dietary Pattern Lowered Adiponectin but Not Leptin Concentration of Breast Cancer Survivors.
    Nutrients, 2021, Sep-24, Volume: 13, Issue:10

    Dietary pattern (DP) and its relationship with disease biomarkers have received recognition in nutritional epidemiology investigations. However, DP relationships with adipokines (i.e., adiponectin and leptin) among breast cancer survivors remain unclear. Therefore, we assessed relationships between DP and high-molecular weight (HMW) adiponectin and leptin concentration among breast cancer survivors. This cross-sectional study involved 128 breast cancer survivors who attended the oncology outpatient clinic at two main government hospitals in the East Coast of Peninsular Malaysia. The serum concentration of HMW adiponectin and leptin were measured using enzyme-linked immunosorbent assay (ELISA) kits. A reduced rank regression method was used to analyze DP. Relationships between DP with HMW adiponectin and leptin were examined using regression models. The findings show that with every 1-unit increase in the 'energy-dense, high-SFA, low-fiber' DP z-score, there was a reduction by 0.41 μg/mL in HMW adiponectin which was independent of age, BMI, education level, occupation status, cancer stage, and duration since diagnosis. A similar relationship with leptin concentration was not observed. In conclusion, the 'energy-dense, high-saturated fat and low-fiber' DP, which is characterized by high intake levels of sugar-sweetened drinks and fat-based spreads but low intake of fruits and vegetables, is an unhealthy dietary pattern and unfavorable for HMW adiponectin concentration, but not for leptin. These findings could serve as a basis in developing specific preventive strategies that are tailored to the growing population of breast cancer survivors.

    Topics: Adiponectin; Adult; Aged; Breast Neoplasms; Cancer Survivors; Dietary Fiber; Fatty Acids; Female; Humans; Leptin; Middle Aged; Regression Analysis

2021
Improving breast cancer prediction using a pattern recognition network with optimal feature subsets.
    Croatian medical journal, 2021, Oct-31, Volume: 62, Issue:5

    To predict the presence of breast cancer by using a pattern recognition network with optimal features based on routine blood analysis parameters and anthropometric data.. Sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC), and Fowlkes-Mallows (FM) index of each model were calculated. Glucose, insulin, age, homeostatic model assessment, leptin, body mass index (BMI), resistin, adiponectin, and monocyte chemoattractant protein-1 were used as predictors.. Pattern recognition network distinguished patients with breast cancer disease from healthy people. The best classification performance was obtained by using BMI, age, glucose, resistin, and adiponectin, and in a model with two hidden layers with 11 and 100 neurons in the neural network. The accuracy, sensitivity, specificty, FM index, and MCC values of the best model were 94.1%, 100%, 88.9%, 94.3%, and 88.9%, respectively.. Breast cancer diagnosis was succesfully predicted using only five features. A model using a pattern recognition network with optimal feature subsets proposed in this study could be used to improve the early detection of breast cancer.

    Topics: Adiponectin; Body Mass Index; Breast Neoplasms; Female; Humans; Insulin; Insulin Resistance; Leptin; Resistin

2021
Association of circulating leptin, adiponectin, and resistin concentrations with long-term breast cancer prognosis in a German patient cohort.
    Scientific reports, 2021, 12-07, Volume: 11, Issue:1

    Adipokines including leptin, adiponectin and resistin have been linked to risk of obesity-related cancers potentially through low-grade chronic inflammation pathways. We aimed to assess the role of post-diagnosis circulating adipokines on long-term prognosis in a prospective breast cancer cohort. Adipokines were measured in blood collected at baseline shortly after diagnosis (2002-2005) and at follow-up (2009) from 3112 breast cancer patients enrolled in the population-based MARIE study. Half of the patients had measurements at both time-points. All-cause mortality, breast cancer specific mortality and recurrences were ascertained up to June 2015 (11 years median follow-up). Associations with time-varying adipokine concentrations overall and stratified by estrogen and progesterone receptor (ERPR) were evaluated using adjusted proportional hazard regression. At baseline (n = 2700) and follow-up (n = 2027), median concentrations for leptin, adiponectin and resistin were 4.6 and 2.7 ng/ml, 24.4 and 30.0 mg/l, 15.4 and 26.2 ng/ml, respectively. After adjustment, there was no evidence for associations between adipokines and any outcome overall. In ERPR negative tumors, highest vs. lowest quintile of adiponectin was significantly associated with increased breast cancer specific mortality (HR 2.51, 95%CI 1.07-5.92). Overall, post-diagnosis adipokines were not associated with long-term outcomes after breast cancer. In patients with ERPR negative tumors, higher concentrations of adiponectin may be associated with increased breast cancer specific mortality and warrant further investigation.

    Topics: Adiponectin; Breast; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Middle Aged; Prognosis; Prospective Studies; Receptors, Estrogen; Receptors, Progesterone; Resistin

2021
Combination of Endogenous Estradiol and Adipokine Leptin in Breast Cancer Risk and Prognosis Assessment in Postmenopausal Chinese Women.
    Frontiers in endocrinology, 2021, Volume: 12

    Our study aims to clarify the role of estradiol and leptin in breast cancer risk and prognostic assessment in postmenopausal Chinese women.. The serum circulating estradiol and leptin level was detected by ELISA. Then the correlation between estradiol, leptin level, and clinical characteristics was analyzed using Fisher's exact test. Next, the Kaplan-Meier model was used to analyze the association between estradiol, leptin, and prognosis of postmenopausal breast cancer patients in our cohort and the TCGA dataset.. The study was conducted at the National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College.. A total of 182 postmenopausal breast cancer patients and 111 healthy subjects from January 2010 to August 2010 were included in the analysis. Another 702 cases with breast cancer were retrieved from The Cancer Genome Atlas (TCGA) database for subsequent analysis.. Serum circulating estradiol and leptin level.. The level of estradiol was significantly higher (. Circulating estradiol and leptin played important roles in the risk of postmenopausal breast cancer even in low-estrogen nations with an independent expression of ER status. High circulating estradiol was a poor prognostic factor and leptin may be a protection signal in Chinese postmenopausal patients with breast cancer.

    Topics: Adipokines; Asian People; Breast Neoplasms; Estradiol; Female; Humans; Leptin; Middle Aged; Postmenopause; Premenopause; Prognosis; Receptors, Estrogen

2021
Autophagy activation and SREBP-1 induction contribute to fatty acid metabolic reprogramming by leptin in breast cancer cells.
    Molecular oncology, 2021, Volume: 15, Issue:2

    Leptin, a hormone predominantly derived from adipose tissue, is well known to induce growth of breast cancer cells. However, its underlying mechanisms remain unclear. In this study, we examined the role of reprogramming of lipid metabolism and autophagy in leptin-induced growth of breast cancer cells. Herein, leptin induced significant increase in fatty acid oxidation-dependent ATP production in estrogen receptor-positive breast cancer cells. Furthermore, leptin induced both free fatty acid release and intracellular lipid accumulation, indicating a multifaceted effect of leptin in fatty acid metabolism. These findings were further validated in an MCF-7 tumor xenograft mouse model. Importantly, all the aforementioned metabolic effects of leptin were mediated via autophagy activation. In addition, SREBP-1 induction driven by autophagy and fatty acid synthase induction, which is mediated by SREBP-1, plays crucial roles in leptin-stimulated metabolic reprogramming and are required for growth of breast cancer cell, suggesting a pivotal contribution of fatty acid metabolic reprogramming to tumor growth by leptin. Taken together, these results highlighted a crucial role of autophagy in leptin-induced cancer cell-specific metabolism, which is mediated, at least in part, via SREBP-1 induction.

    Topics: Animals; Autophagy; Breast Neoplasms; Cellular Reprogramming; Fatty Acids; Female; Humans; Leptin; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Sterol Regulatory Element Binding Protein 1

2021
Fluctuations in depression and anxiety predict dysregulated leptin among obese breast cancer survivors.
    Journal of cancer survivorship : research and practice, 2021, Volume: 15, Issue:6

    Leptin influences inflammation and tumor growth and leptin signaling is often dysregulated among obese breast cancer survivors. This leads to a lack of satiety and, ultimately, risk for further weight gain. Breast cancer survivors also experience high rates of depression and anxiety, which are linked to leptin production. This study examined how a woman's anxiety and depressive symptoms, in combination with their obesity status, were associated with leptin.. Breast cancer survivors (n = 200, stages 0-IIIa) completed a baseline visit before treatment and two follow-up visits, 6 and 18 months after treatment ended. Women completed anxiety and depression measures, and blood samples provided leptin data at each visit. This study related fluctuations in a survivor's own depression and anxiety (i.e., within-person effects), as well as average effects of depression and anxiety (i.e., between-person effects) to changes in leptin depending on BMI.. Obese survivors' leptin was significantly higher at visits when they had higher anxiety and depression symptoms than their own average level of symptoms. In contrast, within-person fluctuations in depression and anxiety were not related to leptin levels among non-obese survivors. No significant between-person effects of depression or anxiety on leptin emerged.. Leptin is a critical risk factor for recurrence and further health consequences. Our findings highlight how psychological health influences leptin production among breast cancer survivors.. These results highlight a biological pathway that may facilitate further weight gain and health risks among distressed, obese breast cancer survivors.

    Topics: Anxiety; Breast Neoplasms; Cancer Survivors; Depression; Female; Humans; Leptin; Obesity; Survivors

2021
Roles of adiponectin and leptin signaling-related microRNAs in the preventive effects of calorie restriction in mammary tumor development.
    Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme, 2021, Volume: 46, Issue:8

    Topics: Adiponectin; Animals; Breast Neoplasms; Caloric Restriction; Disease Models, Animal; Female; Leptin; Mice; Mice, Inbred C57BL; MicroRNAs; Signal Transduction

2021
LEP (-2548G>A LEP) and LEPR (223Gln>Arg, 109Lys>Arg) polymorphisms as breast cancer risk factors in the Polish female population.
    Molecular biology reports, 2021, Volume: 48, Issue:4

    On a global scale, breast cancer is the most common type of cancer in women, and it is still a growing problem. Therefore, new prognostic or diagnostic markers are required that would facilitate the assessment of patients or provide more efficient therapy, respectively. In these studies, we analyzed the contribution of LEP (2548G>A) and LEPR (109 Lys>Arg and 223Gln>Arg) genes polymorphisms to the risk of breast cancer development. The study involved 209 women aged 59.6 ± 11 years diagnosed with breast cancer and 202 healthy women aged 57.8 ± 8.2 years, who were blood donors. Polymorphism were evaluated by PCR-RFLP reaction followed by the verification of part of the samples by sequencing. The results of the study confirmed obesity as a significant breast cancer development risk factor in Polish women. However, no significant association between the studied polymorphisms and breast cancer risk or severity of the neoplastic disease was found. Interestingly, it was shown that wild type 223Gln>Gln leptin receptor (LEPR) was statistically more common in women with human epidermal growth factor receptor 2 negative (HER2-) than human epidermal groth factor receptor 2 positive (HER2+) breast cancer and wild type form of 2548G>A LEP was more common in women with progesterone receptor positive (PR+) than progesterone receptor negative (PR-) breast cancer. Studied polymorphisms of the LEP and LEPR genes do not increase breast cancer risk in the population of Polish women. However, they can affect PR an HER receptors expression and thus the severity of the disease. Noteworthy, this interesting correlation is being reported for the first time and might constitute an essential contribution to the identification of molecular mechanisms of carcinogenesis.

    Topics: Aged; Breast Neoplasms; Case-Control Studies; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Obesity; Patient Acuity; Poland; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors

2021
STAT3 Activation-Induced Fatty Acid Oxidation in CD8
    Cell metabolism, 2020, 01-07, Volume: 31, Issue:1

    Although obesity is known to be critical for cancer development, how obesity negatively impacts antitumor immune responses remains largely unknown. Here, we show that increased fatty acid oxidation (FAO) driven by activated STAT3 in CD8

    Topics: Adipocytes; Adipose Tissue; Animals; Breast Neoplasms; Carcinogenesis; CD8-Positive T-Lymphocytes; Cell Line; Cell Proliferation; Chromatin Immunoprecipitation; Fatty Acids; Female; Glycolysis; Humans; Interferon-gamma; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Obesity; Oxidation-Reduction; Programmed Cell Death 1 Receptor; STAT3 Transcription Factor

2020
Leptin Signaling Contributes to Aromatase Inhibitor Resistant Breast Cancer Cell Growth and Activation of Macrophages.
    Biomolecules, 2020, 04-03, Volume: 10, Issue:4

    Obesity represents a risk factor for breast cancer development and therapy resistance, but the molecular players underling these links are unclear. Here, we identify a role for the obesity-cytokine leptin in sustaining aromatase inhibitor (AI) resistant growth and progression in breast cancer. Using as experimental models MCF-7 breast cancer cells surviving long-term treatment with the AI anastrozole (AnaR) and Ana-sensitive counterparts, we found that AnaR cells expressed higher levels of leptin and its receptors (ObR) along with a constitutive activation of downstream effectors. Accordingly, leptin signaling inhibition reduced only AnaR cell growth and motility, highlighting the existence of an autocrine loop in mechanisms governing drug-resistant phenotypes. In agreement with ObR overexpression, increasing doses of leptin were able to stimulate to a greater extent growth and migration in AnaR than sensitive cells. Moreover, leptin contributed to enhanced crosstalk between AnaR cells and macrophages within the tumor microenvironment. Indeed, AnaR, through leptin secretion, modulated macrophage profiles and increased macrophage motility through CXCR4 signaling, as evidenced by RNA-sequencing, real-time PCR, and immunoblotting. Reciprocally, activated macrophages increased AnaR cell growth and motility in coculture systems. In conclusion, acquired AI resistance is accompanied by the development of a leptin-driven phenotype, highlighting the potential clinical benefit of targeting this cytokine network in hormone-resistant breast cancers, especially in obese women.

    Topics: Anastrozole; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Leptin; Macrophage Activation; Macrophages; MCF-7 Cells; Receptors, CXCR4; Signal Transduction

2020
Biochemical study on modifying role of variants of leptin gene and its receptor on serum leptin levels in breast cancer.
    Molecular biology reports, 2020, Volume: 47, Issue:5

    The leptin is discharged from breast adipose tissue and is overexpressed in breast cancer (BC). Conflicting relation of leptin with BC was reported. We investigated this association and its impact on leptin level and disease characteristics. The study included 70 females (40 women with pathological proof of invasive BC patients and 30 controls). LEP and LEPR polymorphisms were evaluated by real-time PCR. Serum leptin was estimated by ELISA. Both LEPR and LEP disturbances increase the danger of BC where GG genotype and G allele frequencies of LEPR were higher in patients vs. control. GG genotype increases BC risk with OR (9.1) while G allele predisposes to disease with OR (3.8). Furthermore, LEP A allele was uniquely elevated in patients than healthy ones with OR (2.06). Precise relation of circulating leptin and its polymorphisms with predicting BC may authorize its utilization in early screening.

    Topics: Adult; Alleles; Breast Neoplasms; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Factors

2020
Obesity-Altered Adipose Stem Cells Promote Radiation Resistance of Estrogen Receptor Positive Breast Cancer through Paracrine Signaling.
    International journal of molecular sciences, 2020, Apr-15, Volume: 21, Issue:8

    Obesity is associated with poorer responses to chemo- and radiation therapy for breast cancer, which leads to higher mortality rates for obese women who develop breast cancer. Adipose stem cells (ASCs) are an integral stromal component of the tumor microenvironment (TME). In this study, the effects of obesity-altered ASCs (obASCs) on estrogen receptor positive breast cancer cell's (ER

    Topics: Adipose Tissue; Animals; Apoptosis; Breast Neoplasms; Cell Proliferation; Cell Survival; Coculture Techniques; DNA Damage; Female; Gene Knockdown Techniques; Humans; Interleukin-6; Leptin; MCF-7 Cells; Mesenchymal Stem Cells; Mice; Obesity; Oxidative Stress; Paracrine Communication; Radiation; Receptors, Estrogen; Receptors, Notch; RNA, Small Interfering; S Phase Cell Cycle Checkpoints; Signal Transduction; Tumor Microenvironment; Xenograft Model Antitumor Assays

2020
Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer.
    International journal of molecular sciences, 2020, May-27, Volume: 21, Issue:11

    Estrogen-receptor-negative breast cancer (BCER-) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER- progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER- patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER- patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER- patients. Targeting OBR signaling could improve chemotherapeutic efficacy.

    Topics: Breast Neoplasms; Cell Line; Cell Line, Tumor; Cyclin-Dependent Kinase 8; Drug Resistance, Neoplasm; Female; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Leptin; Nanog Homeobox Protein; Receptors, Estrogen; Receptors, Leptin; Signal Transduction; Survival Analysis

2020
Adipokines expression and epithelial cell polarity in normal and cancerous breast tissue.
    Carcinogenesis, 2020, 10-15, Volume: 41, Issue:10

    Cell polarity is crucial for the correct structural and functional organization of epithelial tissue. Its disruption can lead to loss of the apicobasal polarity, alteration in the intracellular components, misregulation of the pathways involved in cell proliferation and cancer promotion. Very recent in vitro/in vivo findings demonstrated that obesity-associated alterations in tissue adipokines protein level negatively affect epithelial polarity. We performed an in silico study to investigate whether such alterations also occur in surgical samples. We aimed to explore the relationship among the expression of the genes coding for leptin (LEP), adiponectin (ADIPOQ), adipokine receptors (LEPR, ADIPOR1 and ADIPOR2), and a panel of polarity-associated genes in normal tissue from breast reduction mammoplasty, and a series of paired samples of histologically normal (HN) tissue and invasive cancer. Results indicated that, in normal tissue, the expression of adipokines and their receptors negatively correlated with that of the polarity-associated genes and GGT1, which codes for γ-glutamyl transferase (GGT) enzyme, a marker of cell distress and membrane disruption. This negative correlation progressively decreased in HN and cancerous tissue, and loss of correlation between ADIPOR2 and polarity-associated genes appeared the most noticeable alteration. Given the growing role of obesity in breast cancer etiology and the opposite action of leptin and adiponectin in epithelial tissue remodeling, ADIPOR2 loss could be addressed as a key mechanism leading to an unbalanced leptin stimulatory activity, subsequent cell polarity disruption and eventually tumor initiation, a finding that requires to be confirmed also at the protein level and with in vivo models.

    Topics: Adipokines; Adiponectin; Breast; Breast Neoplasms; Cell Polarity; Computer Simulation; Epithelial Cells; Female; gamma-Glutamyltransferase; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mammaplasty; Receptors, Adipokine; Receptors, Leptin; Transcriptome

2020
Fasting-mimicking diet and hormone therapy induce breast cancer regression.
    Nature, 2020, Volume: 583, Issue:7817

    Topics: Animals; Biological Factors; Breast Neoplasms; Diet Therapy; Diet, Healthy; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Early Growth Response Protein 1; Fasting; Female; Fulvestrant; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; Piperazines; PTEN Phosphohydrolase; Pyridines; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Xenograft Model Antitumor Assays

2020
Leptin promotes bone metastasis of breast cancer by activating the SDF-1/CXCR4 axis.
    Aging, 2020, 08-18, Volume: 12, Issue:16

    Topics: Adult; Bone Neoplasms; Breast Neoplasms; Cell Movement; Chemokine CXCL12; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Middle Aged; Neoplasm Invasiveness; Receptors, CXCR4; Receptors, Leptin; Signal Transduction

2020
The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors.
    Cells, 2020, 10-01, Volume: 9, Issue:10

    Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer. Leptin is a marker of obesity and promotes breast carcinogenesis through several mechanisms. In this study, we leverage public gene expression datasets to evaluate the associations between FGFR1, leptin, and the leptin receptor (LepR) in breast cancer. We show a positive association between FGFR1 and leptin protein copy number in primary breast tumors. These observations coincided with a positive association between Janus kinase 2 (Jak2) mRNA with both leptin receptor (LepR) mRNA and FGFR1 mRNA. Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A transformation. These results demonstrate how elevated sera FGF2 and leptin in obese patients may promote cancer progression in tumors that express elevated FGFR1 and LepR through Jak2 signaling. Therefore, Jak2 is a potential therapeutic target for FGFR1 amplified breast cancer, especially in the context of obesity.

    Topics: Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Leptin

2020
Blocking leptin-STAT3 axis-induced fatty acid oxidation: A novel approach to activate CD8
    Thoracic cancer, 2020, Volume: 11, Issue:12

    Topics: Breast Neoplasms; CD8-Positive T-Lymphocytes; Cell Self Renewal; Drug Resistance, Neoplasm; Fatty Acids; Humans; Leptin; STAT3 Transcription Factor

2020
Effects of obesity on NK cells in a mouse model of postmenopausal breast cancer.
    Scientific reports, 2020, 11-26, Volume: 10, Issue:1

    Obesity is a widely spread disease and a crucial risk factor for malign disorders, including breast cancer of women in the postmenopause. Studies demonstrated that in case of obesity crucial natural killer (NK) cell functions like combating tumor cells are affected. This study aims to analyze NK cells and NK cell receptor expression of obese mice in a model for postmenopausal breast cancer. Therefore, female BALB/c mice were fed either a high fat or a standard diet. Thereafter, ovaries were ectomized and a syngeneic and orthotopical injection of 4T1-luc2 mouse mammary tumor cells into the mammary adipose tissue pad was performed. Obese mice showed increased body weights and visceral fat mass as well as increased levels of leptin and IL-6 in plasma. Moreover, compared to the lean littermates, tumor growth was increased and the NKp46-expression on circulating NK cells was decreased. Furthermore, the activating NK cell receptor NKG2D ligand (MULT1) expression was enhanced in adipose tissue of obese tumor bearing mice. The present study gives novel insights into gene expression of NK cell receptors in obesity and aims to promote possible links of the obesity-impaired NK cell physiology and the elevated breast cancer risk in obese women.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Disease Models, Animal; Female; Histocompatibility Antigens Class I; Interleukin-6; Killer Cells, Natural; Leptin; Mammary Neoplasms, Animal; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Obese; Obesity; Postmenopause

2020
Characterization of the Relationship Between the Expression of Aspartate β-Hydroxylase and the Pathological Characteristics of Breast Cancer.
    Medical science monitor : international medical journal of experimental and clinical research, 2020, Dec-31, Volume: 26

    BACKGROUND This study aimed to investigate the relationship between the expression of aspartate b-hydroxylase (ASPH) and the molecular mechanisms of ASPH-related genes in breast cancer (BC). MATERIAL AND METHODS ASPH expression was determined by immunohistochemistry and western blot analysis in samples of BC tissues and adjacent normal tissues. ASPH mRNA expression data and their clinical significance in BC were retrieved from the Oncomine and GEPIA datasets. Enrichment analysis of genes coexpressed with ASPH and annotation of potential pathways were performed with Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis. Hub genes were shown in an ASPH coexpression gene-interaction network. The expression of the hub genes associated with patient survival were analyzed to determine the role of ASPH in the progression of BC. RESULTS ASPH levels were overexpressed in BC and correlated with cancer type, lymph node involvement, and TNM stage. Conversely, ASPH levels did not correlate with patient age, invasive carcinoma types, or molecular subtypes. Enrichment analysis showed the involvement of multiple pathways, including lipid metabolism and oxidation-reduction processes. Six hub genes, PPARG, LEP, PLIN1, AGPAT2, CAV1, and PNPLA2, were related to ASPH expression and had functional roles in the occurrence and progression of BC. CONCLUSIONS ASPH may be involved in the development of BC and may have utility as a prognostic biomarker in BC. The coexpression of ASPH-associated genes may also be beneficial in improving BC prognosis.

    Topics: Acyltransferases; Adult; Aged; Atlases as Topic; Breast Neoplasms; Calcium-Binding Proteins; Carcinoma, Ductal, Breast; Caveolin 1; Datasets as Topic; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Gene Ontology; Gene Regulatory Networks; Humans; Leptin; Lipase; Membrane Proteins; Metabolic Networks and Pathways; Middle Aged; Mixed Function Oxygenases; Molecular Sequence Annotation; Muscle Proteins; Neoplasm Staging; Perilipin-1; PPAR gamma; Prognosis; RNA, Messenger; Survival Analysis

2020
Association of single nucleotide polymorphisms of adiponectin and leptin genes with breast cancer.
    Molecular biology reports, 2019, Volume: 46, Issue:6

    Single nucleotide polymorphisms (SNPs) in adiponectin gene [rs1501299 (+276G/T) and rs266729 (-11377C/G)] and one SNP of leptin gene [rs7799039 (-2548G/A)] are known to influence plasma levels of adiponectin and leptin respectively. Literature is scarce on the association of adiponectin gene polymorphism rs266729 with breast cancer. The present study was taken up to study these polymorphisms and their association with breast cancer. Ninety-three patients diagnosed with malignant breast cancer were included as cases along with 186 age matched healthy controls. Adiponectin +276G/T, -11377C/G and leptin -2548G/A polymorphism were studied using polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP). Adipokine levels in blood were measured using enzyme linked immunosorbent assay. Adiponectin +276G/T and leptin -2548G/A showed a significant increased risk for breast cancer even after adjusting for confounding variables like present age, age at menarche, age at first child birth and age at menopause. In the subset analysis, based on menopausal state, stronger association was observed between SNP in adiponectin gene +276G/T with the breast cancer in post-menopausal women after adjusting for all other variables. No association was found with adiponectin -11377C/G. No association of the gene polymorphisms with adipokine levels was observed. Also, no significant association was seen for the effect of gene-environment interaction i.e. presence of polymorphism with obesity and menopausal state for any of the SNPs studied. Adiponectin +276G/T is strongly associated with breast cancer in postmenopausal women while leptin -2548G/A polymorphisms is significantly associated with breast cancer irrespective of the menopausal state in south Indian subjects.

    Topics: Adiponectin; Adult; Aged; Alleles; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Female; Gene Frequency; Gene-Environment Interaction; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Mammography; Middle Aged; Neoplasm Staging; Polymorphism, Single Nucleotide; Risk Factors

2019
Hormonal Therapy Resistance and Breast Cancer: Involvement of Adipocytes and Leptin.
    Nutrients, 2019, Nov-20, Volume: 11, Issue:12

    Obesity, a recognized risk factor for breast cancer in postmenopausal women, is associated with higher mortality rates regardless of menopausal status, which could in part be explained by therapeutic escape. Indeed, adipose microenvironment has been described to influence the efficiency of chemo- and hormonal therapies. Residual cancer stem cells could also have a key role in this process. To understand the mechanisms involved in the reduced efficacy of hormonal therapy on breast cancer cells in the presence of adipose secretome, human adipose stem cells (hMAD cell line) differentiated into mature adipocytes were co-cultured with mammary breast cancer cells and treated with hormonal therapies (tamoxifen, fulvestrant). Proliferation and apoptosis were measured (fluorescence test, impedancemetry, cytometry) and the gene expression profile was evaluated. Cancer stem cells were isolated from mammospheres made from MCF-7. The impact of chemo- and hormonal therapies and leptin was evaluated in this population. hMAD-differentiated mature adipocytes and their secretions were able to increase mammary cancer cell proliferation and to suppress the antiproliferative effect of tamoxifen, confirming previous data and validating our model. Apoptosis and cell cycle did not seem to be involved in this process. The evaluation of gene expression profiles suggested that STAT3 could be a possible target. On the contrary, leptin did not seem to be involved. The study of isolated cancer stem cells revealed that their proliferation was stimulated in the presence of anticancer therapies (tamoxifen, fulvestrant, doxorubicine) and leptin. Our study confirmed the role of adipocytes and their secretome, but above all, the role of communication between adipose and cancer cells in interfering with the efficiency of hormonal therapy. Among the pathophysiological mechanisms involved, leptin does not seem to interfere with the estrogenic pathway but seems to promote the proliferation of cancer stem cells.

    Topics: Adipocytes; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Communication; Cell Proliferation; Coculture Techniques; Drug Resistance, Neoplasm; Female; Fulvestrant; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Neoplastic Stem Cells; Signal Transduction; STAT3 Transcription Factor; Tamoxifen; Tumor Microenvironment

2019
Modulation of the leptin receptors expression in breast cancer cell lines exposed to leptin and tamoxifen.
    Scientific reports, 2019, 12-16, Volume: 9, Issue:1

    One of the factors that has increased the incidence and worse prognosis of breast cancer is obesity. In this condition, high amounts of leptin are secreted, which have proliferative, mitogenic, antiapoptotic, and proinflammatory activity that may be antagonistic to treatment with tamoxifen, considered the first choice. The modulation evaluation of leptin receptor expression in the presence of leptin and tamoxifen stimuli was performed in breast cancer cell lines MCF 7, MDA MB 231 and HCC 1937 as a model of initial approach for the study of breast cancer subtypes and their behavior to the action response of adipokines and their possible relationship with the mechanism of resistance to chemotherapeutics such as tamoxifen in ER positive cell lines and triple negative marker. It was determined that leptin increases the proliferation of the three breast cancer cell lines and tamoxifen is able to exert an antiproliferative effect on them, however, it was identified that the ability of tamoxifen to decrease the proliferation of cancer cells is diminished in the presence of leptin, in addition to changes in the modulation of the expression of its receptor. It was determined that tamoxifen induces a greater modulation of the expression of ObRb in cell lines, which may be related to the decrease of its antiproliferative activity, while leptin generates a proliferative effect in the three cell lines and could participate in the tamoxifen treatment resistance mechanism.

    Topics: Adipokines; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Receptors, Leptin; Tamoxifen

2019
Leptin stimulates IGF-1 transcription by activating AP-1 in human breast cancer cells.
    BMB reports, 2019, Volume: 52, Issue:6

    Leptin, an adipokine regulating energy metabolism, appears to be associated with breast cancer progression. Insulin-like growth factor-1 (IGF-1) mediates the pathogenesis of breast cancer. The regulation of IGF-1 expression by leptin in breast cancer cells is unclear. Here, we found that leptin upregulates IGF-1 expression at the transcriptional level in breast cancer cells. Activating protein-1 (AP-1)-binding element within the proximal region of IGF-1 was necessary for leptin-induced IGF-1 promoter activation. Forced expression of AP-1 components, c-FOS or c-JUN, enhanced leptin-induced IGF-1 expression, while knockdown of c-FOS or c-JUN abrogated leptin responsiveness. All three MAPKs (ERK1/2, JNK1/2, and p38 MAPK) mediated leptin-induced IGF-1 expression. These results suggest that leptin contributes to breast cancer progression through the transcriptional upregulation of leptin via the MAPK pathway. [BMB Reports 2019; 52(6): 385-390].

    Topics: Breast Neoplasms; Cell Line, Tumor; Disease Progression; Female; Humans; Insulin-Like Growth Factor I; Leptin; MCF-7 Cells; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Signal Transduction; Transcription Factor AP-1; Transcriptional Activation; Up-Regulation

2019
Leptin is a direct transcriptional target of EGR1 in human breast cancer cells.
    Molecular biology reports, 2019, Volume: 46, Issue:1

    Leptin is a cytokine that regulates energy metabolism. Leptin can promote breast cancer progression in obese women. However, the mechanism of regulation of leptin expression in breast cancer cells is unclear. Tumor necrosis factor-alpha (TNF-α) stimulated the transcription of the leptin gene. Using mutant promoter constructs, we demonstrated that the EGR1-binding motif in the proximal region of the leptin gene is required for leptin transcription by TNF-α. Forced expression of EGR1 stimulated leptin promoter activity, whereas silencing of EGR1 by RNA interference reduced TNF-α-induced leptin protein accumulation. The ERK1/2 pathway contributed to the expression of EGR1 and leptin by TNF-α. Our results suggest that EGR1 targets the leptin gene in response to TNF-α stimulation in breast cancer cells.

    Topics: Binding Sites; Breast Neoplasms; Cell Line, Tumor; DNA-Binding Proteins; Early Growth Response Protein 1; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MAP Kinase Signaling System; Promoter Regions, Genetic; RNA, Messenger; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Tumor Necrosis Factor-alpha

2019
Growth of breast cancer cells by leptin is mediated via activation of the inflammasome: Critical roles of estrogen receptor signaling and reactive oxygen species production.
    Biochemical pharmacology, 2019, Volume: 161

    Leptin, a hormone primarily derived from adipose tissue, is known to induce tumor growth, but its underlying mechanisms of action are not clearly understood. Inflammasomes, acting as signaling platforms for controlling inflammatory responses, modulate tumor growth in a complicated manner. In this study, we investigated the role of inflammasomes in leptin-induced growth of breast cancer cells. Herein, we showed that leptin activated NLRP3 inflammasomes in MCF-7 breast cancer cells, as determined by activation of caspase-1, maturation of interleukin-1β, and increased expression of the inflammasome components, including NLRP3 and ASC. Interestingly, inhibition of the inflammasome by treatment with a pharmacological inhibitor of caspase-1 or gene silencing of NLRP3 prevented leptin-induced increase in cell viability. Moreover, suppression of apoptosis and cell cycle promotion by leptin were also significantly abolished by gene silencing of NLRP3, clearly indicating a crucial role of NLRP3 inflammasomes in leptin-induced breast cancer growth. In addition, inhibition of estrogen receptor signaling or ROS production markedly blocked leptin-induced activation of NLRP3 inflammasomes, suggesting that estrogen receptor signaling and ROS production mediate inflammasomes activation by leptin. The stimulatory effect of leptin on inflammasomes activation was also observed in MCF-7 tumor xenograft model. Furthermore, the critical roles of inflammasomes activation in leptin-induced tumor growth, suppression of apoptotic gene expression, and induction of the genes stimulating cell cycle were confirmed in a tumor xenograft model. Taken together, these results demonstrate that inflammasomes activation plays a pivotal role in leptin-induced growth of breast cancer cells via modulation of both apoptosis and cell cycle.

    Topics: Animals; Breast Neoplasms; Cell Proliferation; Cell Survival; Female; Humans; Leptin; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Receptors, Estrogen; Signal Transduction; Xenograft Model Antitumor Assays

2019
Deregulated microRNAs and Adiponectin in Postmenopausal Women with Breast Cancer.
    Gynecologic and obstetric investigation, 2019, Volume: 84, Issue:4

    Obesity is a risk factor for breast cancer (BC). Some mechanisms through which obesity can lead to cancer development are insulin-like growth factors (IGFs), adipokines, and microRNAs (miRs). The objective of the study was to determine whether miR-17-5p, miR-195-5p, and miR-221-3p expressions were deregulated in serum samples of obese and nonobese postmenopausal women with BC. In addition, insulin, adiponectin, leptin and IGFs were analyzed.. Fifty postmenopausal women with newly diagnosed BC and 50 postmenopausal healthy women were evaluated. Differences in miRs between BC and healthy cases and between obese and lean participants were analyzed. Receiver operating characteristic curves for miRs for discriminating patients with or without BC were established, and relationships between the miRs, adipokines, and breast tumor characteristics were also investigated.. miR-17-5p and miR-195-5p were higher in patients with BC in comparison to the controls, while miR-221-3p and adiponectin were significantly lower. Increased levels of miR-195-5p allowed the differentiation of BC from controls with a sensitivity of 83.3 and a specificity of 78.3%, and were associated with lobular and poorly differentiated cancer. There was no difference in miRs levels between obese and lean groups.. Circulating miRs and adiponectin were deregulated in postmenopausal women with BC.

    Topics: Adiponectin; Adult; Aged; Breast Neoplasms; Female; Humans; Leptin; MicroRNAs; Middle Aged; Obesity; Postmenopause; Risk Factors; ROC Curve; Somatomedins

2019
Elevated leptin disrupts epithelial polarity and promotes premalignant alterations in the mammary gland.
    Oncogene, 2019, Volume: 38, Issue:20

    Obesity is a highly prevalent and modifiable breast cancer risk factor. While the role of obesity in fueling breast cancer progression is well established, the mechanisms linking obesity to breast cancer initiation are poorly understood. A hallmark of breast cancer initiation is the disruption of apical polarity in mammary glands. Here we show that mice with diet-induced obesity display mislocalization of Par3, a regulator of cellular junctional complexes defining mammary epithelial polarity. We found that epithelial polarity loss also occurs in a 3D coculture system that combines acini with human mammary adipose tissue, and establish that a paracrine effect of the tissue adipokine leptin causes loss of polarity by overactivation of the PI3K/Akt pathway. Leptin sensitizes non-neoplastic cells to proliferative stimuli, causes mitotic spindle misalignment, and expands the pool of cells with stem/progenitor characteristics, which are early steps for cancer initiation. We also found that normal breast tissue samples with high leptin/adiponectin transcript ratio characteristic of obesity have an altered distribution of apical polarity markers. This effect is associated with increased epithelial cell layers. Our results provide a molecular basis for early alterations in epithelial architecture during obesity-mediated cancer initiation.

    Topics: Adaptor Proteins, Signal Transducing; Adipokines; Adipose Tissue; Animals; Body Mass Index; Breast Neoplasms; Cell Adhesion Molecules; Cell Cycle Proteins; Disease Models, Animal; Epithelial Cells; Female; Humans; Leptin; Mammary Glands, Animal; Mammary Glands, Human; Mice, Inbred BALB C; Obesity; Precancerous Conditions; Spindle Apparatus

2019
Higher Insulin Resistance and Adiposity in Postmenopausal Women With Breast Cancer Treated With Aromatase Inhibitors.
    The Journal of clinical endocrinology and metabolism, 2019, 09-01, Volume: 104, Issue:9

    Aromatase deficiency causes obesity and insulin resistance in aromatase knockout mice and humans with rare mutations of the aromatase gene (CYP19). Aromatase inhibitors are a commonly prescribed therapy for postmenopausal breast cancer.. We hypothesized that aromatase inhibitors induce obesity and insulin resistance when used in treatment of breast cancer.. Case-control study.. University teaching hospital.. Patients with postmenopausal breast cancer (n = 20) treated with aromatase inhibitors and 20 age-matched control subjects.. The primary outcome measure was insulin sensitivity index - Matsuda, derived from a 75-g oral glucose tolerance test. Body composition was assessed by dual energy x-ray absorptiometry and biopsy specimens of subcutaneous adipose tissue obtained for assessment of mRNA transcript levels. Data are reported as mean ± SEM (patients receiving inhibitors vs control group, respectively).. Aromatase inhibitor therapy was associated with significantly lower insulin sensitivity (5.15 ± 0.45 vs 6.80 ± 0.64; P = 0.041), higher peak insulin concentration after oral glucose tolerance test (693.4 ± 78.6 vs 527.6 ± 85.5 pmol/L; P = 0.035), greater percentage of body fat (38.4% ± 1.0% vs 34.6% ± 1.3%; P = 0.026), and higher plasma leptin concentration (23.5 ± 2.8 vs 15.5 ± 2.3 ng/mL; P = 0.035).. Women who received aromatase inhibitors for postmenopausal breast cancer had greater percentage body fat and insulin resistance compared with control subjects with no history of breast cancer.

    Topics: Adipose Tissue; Adiposity; Aged; Aromatase Inhibitors; Breast Neoplasms; Case-Control Studies; Female; Follow-Up Studies; Glucose Tolerance Test; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Postmenopause; Prognosis

2019
The Effect of the Leptin and Leptin Receptor Expression on the Efficacy of Neoadjuvant Chemotherapy in Breast Cancer.
    Medical science monitor : international medical journal of experimental and clinical research, 2019, Apr-24, Volume: 25

    BACKGROUND The purpose of the present study was to evaluate the effect of leptin and leptin receptor (LEPR) expression on the efficacy of neoadjuvant chemotherapy in breast cancer. MATERIAL AND METHODS There were 325 breast cancer patients with complete data enrolled in this study. Patients were categorized into 3 groups: pathological complete response group, non-pathological complete response group, and progressive disease group. Immunohistochemistry was performed to determine leptin and its receptor LEPR expression levels that were compared among the 3 groups. RESULTS Compared with the non-pathological complete response group, patients in the pathological complete response group had increased leptin and LEPR expression, although the difference was not statistically significant (P=0.194, P=0.110). In addition, the expression of leptin and LEPR in the pathological complete response group was also higher than that in the progressive disease group, and the difference of LEPR expression was statistically significant (P=0.008) while the leptin expression was not (P=0.065). There were more HER2+ breast cancer patients in the pathological complete response group categorized into strong positive, and positive expression of leptin and LEPR compared with the progressive disease group (P<0.05). There were significant differences of leptin and LEPR expression among breast cancer patients under different molecular subtypes HER2+, HR+, and triple negative, in which the triple negative patients had the highest expression of leptin and LEPR. In addition, patients in the progressive disease group had high and low expression of leptin and LEPR: 13.25% versus 11.32% and 13.1% versus 10.42% respectively. CONCLUSIONS Overexpression of leptin and LEPR improved the therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer, especially for those with HER2+ subtype. Overexpression of leptin and LEPR was distinct among the different molecular subtypes of breast cancer, suggesting a certain predictive value for breast cancer prognosis.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Immunohistochemistry; Leptin; Middle Aged; Neoadjuvant Therapy; Prognosis; Receptor, ErbB-2; Receptors, Leptin; Triple Negative Breast Neoplasms

2019
Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: A prospective cohort study.
    Journal of cellular and molecular medicine, 2019, Volume: 23, Issue:6

    Cancer-related fatigue (CRF) is subjective and has wide inter-individual variability. Given that leptin is commonly associated with fatigue syndrome, its use as a potential biomarker for CRF is being investigated. The primary objective of this study was to evaluate the association between leptin and CRF in early-stage breast cancer patients receiving chemotherapy. In a prospective cohort study, patients completed assessments at baseline (T1), during chemotherapy (T2) and after chemotherapy (T3). Levels of plasma leptin and adipokines were measured using a Luminex bead-immunoassay and CRF was measured using the Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Data were analysed longitudinally using a generalised estimating equation incorporating clinically relevant parameters and pro-inflammatory adipokines. The analysis included 136 patients (mean age ± SD = 51.5 ± 8.8 years; 69.1% receiving anthracycline-based chemotherapy). More patients experienced CRF at T3 (23.8%) than at T2 (13.8%) compared to baseline. An increase was observed in the median plasma leptin level at T2, followed by a decrease at T3 (T1: 4.07 ng/mL, T2: 4.95 ng/mL and T3: 3.96 ng/mL). In the multivariate model, the change in leptin levels over time was significantly associated with the total MFSI-SF score (β = -0.15, P = 0.003) after adjusting for the tumour necrosis factor-α (TNF-α) level, anxiety, depression, insomnia, age, menopausal status and type of chemotherapy. This is the first study to report leptin as a biomarker that predicts the onset of CRF over time. Future studies are required to validate the findings.

    Topics: Adipokines; Biomarkers; Breast Neoplasms; C-Reactive Protein; Fatigue; Female; Humans; Leptin; Middle Aged; Neoplasm Staging; Prospective Studies

2019
Metabolic hormones and breast cancer risk among Mexican American Women in the Mano a Mano Cohort Study.
    Scientific reports, 2019, 07-10, Volume: 9, Issue:1

    C-peptide, insulin, leptin, and other metabolic hormones are assumed to play roles in breast cancer development; though, results are inconsistent. In this prospective case-control study nested within the Mano a Mano Cohort Study, we assessed the risk of breast cancer with regard to plasma levels of c-peptide, gastric inhibitory polypeptide, insulin, leptin, monocyte chemoattractant protein-1, pancreatic polypeptide, and peptide YY. Among women followed for a median of 8.5 years, 109 breast cancer cases were identified and frequency-matched to 327 controls at a ratio of 1:3. Overall, only c-peptide was observed significantly associated with breast cancer risk. High c-peptide levels (≥ the median level of controls) were significantly associated with increased breast cancer risk (odds ratio [OR] = 1.39, 95% confidence interval [CI]: 1.01, 2.44). In an analysis of participants stratified by age, the significant association between c-peptide levels and breast cancer risk was evident in only women age ≥51 years (OR = 1.53, 95% CI: 1.02, 3.27). Among women age <51 years, high leptin levels were significantly associated with decreased breast cancer risk (OR = 0.49, 95% CI: 0.24, 0.82). Our findings suggest that selected metabolic hormones are associated with breast cancer development in Mexican American women.

    Topics: Age Factors; Breast Neoplasms; C-Peptide; Case-Control Studies; Chemokine CCL2; Female; Gastric Inhibitory Polypeptide; Humans; Insulin; Leptin; Mexican Americans; Pancreatic Polypeptide; Peptide YY; Prospective Studies; Risk Factors; United States; Up-Regulation

2019
Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link.
    International journal of obesity (2005), 2018, Volume: 42, Issue:4

    Human breast ASCs were used to characterize the p53-HIF1α/PKM2-aromatase axis in response to leptin. The effect of pharmacological or genetic modulation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK), p53, Aha1, Hsp90, HIF1α and PKM2 on aromatase promoter activity, expression and enzyme activity was examined. Semiquantitative immunofluorescence and confocal imaging were used to assess ASC-specific protein expression in formalin-fixed paraffin-embedded tissue sections of breast of women and mammary tissue of mice following a low-fat (LF) or high-fat (HF) diet for 17 weeks.. Leptin-mediated induction of aromatase was dependent on PKC/MAPK signaling and the suppression of p53. This, in turn, was associated with an increase in Aha1 protein expression, activation of Hsp90 and the stabilization of HIF1α and PKM2, known stimulators of aromatase expression. Consistent with these findings, ASC-specific immunoreactivity for p53 was inversely associated with BMI in breast tissue, while HIF1α, PKM2 and aromatase were positively correlated with BMI. In mice, HF feeding was associated with significantly lower p53 ASC-specific immunoreactivity compared with LF feeding, while immunoreactivity for HIF1α, PKM2 and aromatase were significantly higher.. Overall, findings demonstrate a novel mechanism for the obesity-associated increase in aromatase in ASCs of the breast and support the study of lifestyle interventions, including weight management, which may reduce breast cancer risk via effects on this pathway.

    Topics: Adipocytes; Animals; Aromatase; Body Mass Index; Breast; Breast Neoplasms; Carrier Proteins; Cells, Cultured; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Mammary Glands, Animal; Membrane Proteins; Mice; Obesity; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Tumor Suppressor Protein p53

2018
JAK/STAT3-Regulated Fatty Acid β-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance.
    Cell metabolism, 2018, 01-09, Volume: 27, Issue:1

    Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.

    Topics: Adipocytes; Aged; Animals; Breast Neoplasms; Carnitine O-Palmitoyltransferase; Cell Line, Tumor; Cell Self Renewal; Drug Resistance, Neoplasm; Fatty Acids; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinases; Leptin; Lipid Metabolism; Metabolomics; Mice; Middle Aged; Neoplastic Stem Cells; Oxidation-Reduction; Signal Transduction; STAT3 Transcription Factor; Transcription, Genetic

2018
Frontline Science: High fat diet and leptin promote tumor progression by inducing myeloid-derived suppressor cells.
    Journal of leukocyte biology, 2018, Volume: 103, Issue:3

    Obesity is a risk factor for cancer incidence and cancer mortality. The association of obesity and cancer is attributed to multiple factors, but the tightest linkage is with the chronic, low-grade inflammation that accompanies obesity. Myeloid-derived suppressor cells (MDSC) are known facilitators of cancer progression that act by suppressing the activation and function of tumor-reactive T cells. Because MDSC quantity and function are driven by chronic inflammation, we hypothesized that MDSC may accumulate in obese individuals and facilitate tumor growth by suppressing antitumor immunity. To test this hypothesis, tumor-bearing mice on a high fat or low fat diet (HFD or LFD) were assessed for tumor progression and the metabolic dysfunction associated with obesity. HFD enhanced the accumulation of MDSC, and the resulting MDSC had both beneficial and detrimental effects. HFD-induced MDSC protected mice against diet-induced metabolic dysfunction and reduced HFD-associated inflammation, but also increased the accumulation of fat, enhanced tumor progression, and spontaneous metastasis and reduced survival time. HFD-induced MDSC facilitated tumor growth by limiting the activation of tumor-reactive CD8

    Topics: Animals; Breast Neoplasms; Diet, High-Fat; Female; Inflammation; Leptin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Obesity; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2018
Leptin-induced ER-α-positive breast cancer cell viability and migration is mediated by suppressing CCN5-signaling via activating JAK/AKT/STAT-pathway.
    BMC cancer, 2018, 01-25, Volume: 18, Issue:1

    In menopausal women, one of the critical risk factors for breast cancer is obesity/adiposity. It is evident from various studies that leptin, a 16 kDa protein hormone overproduced in obese people, plays the critical role in neovascularization and tumorigenesis in breast and other organs. However, the mechanisms by which obesity influences the breast carcinogenesis remained unclear. In this study, by analyzing different estrogen receptor-α (ER-α)-positive and ER-α-negative BC cell lines, we defined the role of CCN5 in the leptin-mediated regulation of growth and invasive capacity.. We analyzed the effect of leptin on cell viability of ER-α-positive MCF-7 and ZR-75-1 cell lines and ER-α-negative MDA-MB-231 cell line. Additionally, we also determined the effect of leptin on the epithelial-mesenchymal transition (EMT) bio-markers, in vitro invasion and sphere-formation of MCF-7 and ZR-75-1 cell lines. To understand the mechanism, we determined the impact of leptin on CCN5 expression and the functional role of CCN5 in these cells by the treatment of human recombinant CCN5 protein(hrCCN5). Moreover, we also determined the role of JAK-STAT and AKT in the regulation of leptin-induced suppression of CCN5 in BC cells.. Present studies demonstrate that leptin can induce cell viability, EMT, sphere-forming ability and migration of MCF-7 and ZR-75-1 cell lines. Furthermore, these studies found that leptin suppresses the expression of CCN5 at the transcriptional level. Although the CCN5 suppression has no impact on the constitutive proliferation of MCF-7 and ZR-75-1 cells, it is critical for leptin-induced viability and necessary for EMT, induction of in vitro migration and sphere formation, as the hrCCN5 treatment significantly inhibits the leptin-induced viability, EMT, migration and sphere-forming ability of these cells. Mechanistically, CCN5-suppression by leptin is mediated via activating JAK/AKT/STAT-signaling pathways.. These studies suggest that CCN5 serves as a gatekeeper for leptin-dependent growth and progression of luminal-type (ER-positive) BC cells. Leptin may thus need to destroy the CCN5-barrier to promote BC growth and progression via activating JAK/AKT/STAT signaling. Therefore, these observations suggest a therapeutic potency of CCN5 by restoration or treatment in obese-related luminal-type BC growth and progression.

    Topics: Breast Neoplasms; Carcinogenesis; CCN Intercellular Signaling Proteins; Cell Movement; Cell Proliferation; Cell Survival; Estrogen Receptor alpha; Humans; Janus Kinases; Leptin; MCF-7 Cells; Menopause; Neoplasm Invasiveness; Obesity; Proto-Oncogene Proteins c-akt; Repressor Proteins; STAT Transcription Factors

2018
Adipocyte/breast cancer cell crosstalk in obesity interferes with the anti-proliferative efficacy of tamoxifen.
    PloS one, 2018, Volume: 13, Issue:2

    Obesity is a well-known risk factor of breast cancer in post-menopausal women that also correlates with a diminished therapeutic response. The influence of adipocytes and their secretome, i.e. adipokines, on the efficacy of hormone therapy has yet to be elucidated.. We investigated, ex vivo, whether mature adipocytes, differentiated from adipose stem cells of normal-weight (MA20) or obese (MA30) women, and their secretions, were able to counteract the effects of tamoxifen (Tx) which is known to decrease neoplastic cell proliferation.. In a tridimensional model and in a model of co-culture, the anti-proliferative effect of Tx on MCF-7 cancer cells was counteracted by MA30. These two models highlighted two different specific gene expression profiles for genes encoding cytokines or involved in angiogenesis based on the adipocyte microenvironment and the treatment. Thus it notably showed altered expression of genes such as TNFα that correlated with IL-6. In addition, leptin, IL-6 and TNFα, at concentrations reflecting plasma concentrations in obese patients, decreased the anti-proliferative efficacy of 4-hydroxytamoxifen (a major active metabolite of Tx).. These findings bring insights on adipocytes and mammary cancer cell interactions in Tx therapy, particularly in overweight/obese people. Indeed, patient' adipokine status would give valuable information for developing individual strategies and avoid resistance to treatment.

    Topics: Adipocytes; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Line; Cell Proliferation; Female; Gene Expression; Humans; Leptin; MCF-7 Cells; Obesity; Tamoxifen; Tumor Necrosis Factor-alpha

2018
A Role for Hypocretin/Orexin in Metabolic and Sleep Abnormalities in a Mouse Model of Non-metastatic Breast Cancer.
    Cell metabolism, 2018, Jul-03, Volume: 28, Issue:1

    We investigated relationships among immune, metabolic, and sleep abnormalities in mice with non-metastatic mammary cancer. Tumor-bearing mice displayed interleukin-6 (IL-6)-mediated peripheral inflammation, coincident with altered hepatic glucose processing and sleep. Tumor-bearing mice were hyperphagic, had reduced serum leptin concentrations, and enhanced sensitivity to exogenous ghrelin. We tested whether these phenotypes were driven by inflammation using neutralizing monoclonal antibodies against IL-6; despite the reduction in IL-6 signaling, metabolic and sleep abnormalities persisted. We next investigated neural populations coupling metabolism and sleep, and observed altered activity within lateral-hypothalamic hypocretin/orexin (HO) neurons. We used a dual HO-receptor antagonist to test whether increased HO signaling was causing metabolic abnormalities. This approach rescued metabolic abnormalities and enhanced sleep quality in tumor-bearing mice. Peripheral sympathetic denervation prevented tumor-induced increases in serum glucose. Our results link metabolic and sleep abnormalities via the HO system, and provide evidence that central neuromodulators contribute to tumor-induced changes in metabolism.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Ghrelin; Glucose; Hyperphagia; Interleukin-6; Leptin; Mammary Neoplasms, Experimental; Metabolic Diseases; Mice; Mice, Inbred BALB C; Neurons; Orexin Receptor Antagonists; Orexins; Sleep; Sleep Wake Disorders

2018
Changes in metabolic risk, insulin resistance, leptin and adiponectin following a lifestyle intervention in overweight and obese breast cancer survivors.
    European journal of cancer care, 2018, Volume: 27, Issue:4

    Adiposity and physical activity are modifiable factors that could be important determinants of breast cancer (BC) prognosis through their effects on endogenous reproductive hormones, chronic inflammation and metabolic changes. Therefore, it is necessary to evaluate whether offering lifestyle interventions to BC survivors could affect the levels of certain biomarkers involved in these mechanisms. We designed a pre-post intervention study offering diet and exercise sessions over 12 weeks to 42 overweight/obese BC survivors. Before and after the intervention, we obtained dietary information, anthropometry and cardiorespiratory fitness (CRF) measurements and blood samples to measure metabolic risk, insulin resistance and adipokines biomarkers. Wilcoxon signed-rank tests and Spearman partial correlation coefficients were used to compare pre- and post-measurements and assess the correlations between changes in biomarkers and changes in anthropometry and CRF. Breast cancer survivors showed significant improvements in metabolic risk biomarkers and insulin resistance indicators along with a non-significant leptin decrease and a significant adiponectin decrease. The improvements in metabolic risk biomarkers, insulin resistance indicators and leptin were moderately correlated (0.32 ≤ |r| ≤ 0.55) with the decrease in body mass index and the increase in CRF. Diet and exercise interventions implemented in overweight/obese BC survivors may improve metabolic risk, insulin resistance and leptin biomarkers.

    Topics: Adiponectin; Blood Glucose; Body Mass Index; Breast Neoplasms; Cancer Survivors; Cardiorespiratory Fitness; Diet Therapy; Exercise; Female; Humans; Insulin Resistance; Leptin; Middle Aged; Obesity; Overweight; Risk Reduction Behavior

2018
Pro-inflammatory cytokines and growth factors in human milk: an exploratory analysis of racial differences to inform breast cancer etiology.
    Breast cancer research and treatment, 2018, Volume: 172, Issue:1

    Analysis of cytokines and growth factors in human milk offers a noninvasive approach for studying the microenvironment of the postpartum breast, which may better reflect tissue levels than testing blood samples. Given that Black women have a higher incidence of early-onset breast cancers than White women, we hypothesized that milk of the former contains higher levels of pro-inflammatory cytokines, adipokines, and growth factors.. Participants included 130 Black and 162 White women without a history of a breast biopsy who completed a health assessment questionnaire and donated milk for research. Concentrations of 15 analytes in milk were examined using two multiplex and 4 single-analyte electrochemiluminescent sandwich assays to measure pro-inflammatory cytokines, angiogenesis factors, and adipokines. Mixed-effects ordinal logistic regression was used to identify determinants of analyte levels and to compare results by race, with adjustment for confounders. Factor analysis was used to examine covariation among analytes.. Thirteen of 15 analytes were detected in ≥ 25% of the human milk specimens. In multivariable models, elevated BMI was significantly associated with increased concentrations of 5 cytokines: IL-1β, bFGF, FASL, EGF, and leptin (all p-trend < 0.05). Black women had significantly higher levels of leptin and IL-1β, controlling for BMI. Factor analysis of analyte levels identified two factors related to inflammation and growth factor pathways.. This exploratory study demonstrated the feasibility of measuring pro-inflammatory cytokines, adipokines, and angiogenesis factors in human milk, and revealed higher levels of some pro-inflammatory factors, as well as increased leptin levels, among Black as compared with White women.

    Topics: Adult; Biopsy; Black or African American; Breast Neoplasms; Cytokines; Fas Ligand Protein; Female; Fibroblast Growth Factors; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-1beta; Leptin; Milk, Human; Postpartum Period; White People

2018
Time-restricted feeding mitigates high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice.
    Nutrition research (New York, N.Y.), 2018, Volume: 59

    Erratic eating behavior disrupts the daily feeding and fasting pattern and leads to metabolic dysfunction and chronic diseases including cancer. In the present study, we tested the hypothesis that time-restricted feeding of a high-fat diet (HFD) to the dark phase does not enhance mammary tumorigenesis in MMTV-PyMT mice. Female mice were assigned to 3 groups and fed the standard AIN93G diet or an HFD with or without dark phase restricted feeding (12 hours). The duration of restricted feeding was 8 weeks. The HFD group had 24% more body fat mass than the AIN93G group; the body fat mass of the restricted group remained similar to that of the AIN93G group. Energy intake of the restricted group was similar to that of the HFD and AIN93G groups. The median mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the AIN93G, HFD, and restricted groups, respectively. Mammary tumor progression was 241% higher in the HFD group than that in the AIN93G group; there was no significant difference in tumor progression between the restricted and AIN93G groups. Plasma concentrations of leptin, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, angiopoietin-2, vascular endothelial growth factor, and hepatocyte growth factor were significantly higher in the HFD group than those in the control group; these measurements were similar between the restricted and control groups. In conclusion, feeding restricted to the dark phase mitigates the HFD-enhanced mammary tumorigenesis; this may be related to the lower body adiposity and associated inflammatory and angiogenic signals.

    Topics: Adipose Tissue; Adiposity; Angiopoietin-2; Animals; Breast Neoplasms; Carcinogenesis; Chemokine CCL2; Darkness; Diet, High-Fat; Fasting; Feeding Behavior; Female; Hepatocyte Growth Factor; Inflammation; Leptin; Mice, Inbred Strains; Neovascularization, Pathologic; Obesity; Plasminogen Activator Inhibitor 1; Vascular Endothelial Growth Factor A

2018
Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression.
    Cell communication and signaling : CCS, 2018, 12-18, Volume: 16, Issue:1

    Adipocytes make up the major component of breast tissue, accounting for 90% of stromal tissue. Thus, the crosstalk between adipocytes and breast cancer cells may play a critical role in cancer progression. Adipocyte-breast cancer interactions have been considered important for the promotion of breast cancer metastasis. However, the specific mechanisms underlying these interactions are unclear. In this study, we investigated the mechanisms of adipocyte-mediated breast cancer metastasis.. Breast cancer cells were cocultured with mature adipocytes for migration and 3D matrix invasion assays. Next, lentivirus-mediated loss-of-function experiments were used to explore the function of lysyl hydroxylase (PLOD2) in breast cancer migration and adipocyte-dependent migration of breast cancer cells. The role of PLOD2 in breast cancer metastasis was further confirmed using orthotopic mammary fat pad xenografts in vivo. Clinical samples were used to confirm that PLOD2 expression is increased in tumor tissue and is associated with poor prognosis of breast cancer patients. Cells were treated with cytokines and pharmacological inhibitors in order to verify which adipokines were responsible for activation of PLOD2 expression and which signaling pathways were activated in vitro.. Gene expression profiling and Western blotting analyses revealed that PLOD2 was upregulated in breast cancer cells following coculture with adipocytes; this process was accompanied by enhanced breast cancer cell migration and invasion. Loss-of-function studies indicated that PLOD2 knockdown suppressed cell migration and disrupted the formation of actin stress fibers in breast cancer cells and abrogated the migration induced by following coculture with adipocytes. Moreover, experiments performed in orthotopic mammary fat pad xenografts showed that PLOD2 knockdown could reduce metastasis to the lung and liver. Further, high PLOD2 expression correlated with poor prognosis of breast cancer patients. Mechanistically, adipocyte-derived interleukin-6 (IL-6) and leptin may facilitate PLOD2 upregulation in breast cancer cells and promote breast cancer metastasis in tail vein metastasis assays. Further investigation revealed that adipocyte-derived IL-6 and leptin promoted PLOD2 expression through activation of the JAK/STAT3 and PI3K/AKT signaling pathways.. Our study reveals that adipocyte-derived IL-6 and leptin promote PLOD2 expression by activating the JAK/STAT3 and PI3K/AKT signaling pathways, thus promoting breast cancer metastasis.

    Topics: 3T3-L1 Cells; Adipocytes; Adipokines; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Gene Knockdown Techniques; Humans; Interleukin-6; Janus Kinases; Leptin; Mice; Neoplasm Metastasis; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; Prognosis; Proto-Oncogene Proteins c-akt; Signal Transduction; STAT3 Transcription Factor; Tumor Microenvironment; Up-Regulation

2018
Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers.
    The Journal of clinical endocrinology and metabolism, 2017, 05-01, Volume: 102, Issue:5

    Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown.. To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction.. Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention.. Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers.. Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women.. Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

    Topics: Adiponectin; Adipose Tissue, White; Adult; Aged; Aromatase; Blood Glucose; Body Mass Index; Breast; Breast Neoplasms; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Gene Expression Regulation, Developmental; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Leptin; Menopause; Middle Aged; Multivariate Analysis; Postmenopause; Premenopause; RNA, Messenger; Triglycerides

2017
Inhibitory effects of BMP9 on breast cancer cells by regulating their interaction with pre-adipocytes/adipocytes.
    Oncotarget, 2017, May-30, Volume: 8, Issue:22

    Bone morphogenetic protein 9 (BMP9) possesses multiple functions, but its effects on breast cancer cells in adipose microenvironment are still unclear. This study aimed to investigate whether BMP9 is able to modulate the interaction between pre-adipocytes/adipocytes and breast cancer cells. An in vitro co-culture system was established by using pre-adipocytes/adipocytes and MDA-MB-231 breast cancer cells with BMP9 over-expression. The leptin expression and leptin-induced signaling pathway were evaluated in this co-culture system. MTT assay, EdU assay and flow cytometry were used to assess the proliferation of MDA-MB-231 cells. Wound-healing assay and Transwell migration assay were used to assess the migration of MDA-MB-231 cells. Immunofluorescence staining was used to detect the expression of leptin recepter (ObR) in MDA-MB-231 cells. The expression of key molecules in leptin signaling pathway in co-culture system were detected by Western blotting. MDA-MB-231 cells and pre-adipocytes/adipocytes were inoculated into nude mice, the tumor volume was measured, and the protein expression of key molecules in leptin signaling pathway was detected. Results showed BMP9 inhibited breast tumor growth in vitro and in vivo and reduced the migration of breast cancer cells in vitro. MDA-MB-231 cells with BMP9 over-expression decreased leptin expression in pre-adipocytes/adipocytes and had reduced phosphorylation of STAT3, ERK1/2 and AKT. Taken together, our study indicates that BMP9 can inhibit the growth and metastasis of breast cancer cells, which may be related to interaction between pre-adipocytes/adipocytes and MDA-MB-231 cells via leptin signaling pathway.

    Topics: 3T3-L1 Cells; Adipocytes; Animals; Apoptosis; Breast Neoplasms; Cell Communication; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Disease Models, Animal; Female; Gene Expression; Growth Differentiation Factor 2; Heterografts; Humans; Leptin; Mice; Neoplasm Metastasis; Signal Transduction

2017
LEP rs7799039, LEPR rs1137101, and ADIPOQ rs2241766 and 1501299 Polymorphisms Are Associated With Obesity and Chemotherapy Response in Mexican Women With Breast Cancer.
    Clinical breast cancer, 2017, Volume: 17, Issue:6

    Obesity plays a major role in the pathogenesis of breast cancer. Leptin (LEP) and adiponectin (ADIPOQ) are important in the regulation of adipose tissue. The response to cancer treatment depends on the histological and molecular tumor type, clinical stage, and genetic variability that might promote carcinogenic development. The aim of this study was to investigate the association between overweight/obesity and polymorphisms in the LEP (rs7799039), LEP receptor (LEPR; rs1137101), and ADIPOQ genes (rs2241766, rs1501299) with the response to breast cancer treatment in Mexican women.. A sample of 177 patients with primary breast cancer (stage I-III) and who received neoadjuvant therapy were included. Polymorphisms were genotyped and their serum LEP concentrations (n = 59) were quantified.. The patients' median age was 53.1 years, the frequency of overweight and obesity was 57 and 84 patients, respectively, 117 were postmenopausal, and 64 of the patients did not respond to chemotherapy. An association of the LEP rs7799039, LEPR rs1137101, and ADIPOQ rs1501299 polymorphisms with overweight/obesity was found. The patients who did not respond to treatment were more frequently obese, at clinical stage III, had metastases, and high levels of glucose. Moreover, in samples that were positive for estrogen receptor, higher levels of LEP were found, and in wild type genotypes for LEP rs7799039 and LEPR rs1137101.. There was a direct association between the polymorphisms in LEP rs7799039 and ADIPOQ rs1501299 with overweight/obesity, and these genotypes affected the response to chemotherapeutic treatment, suggesting that an obesogenic microenvironment is more favorable for tumoral progression.

    Topics: Adiponectin; Adult; Aged; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Mexico; Middle Aged; Obesity; Polymorphism, Single Nucleotide; Receptors, Leptin

2017
Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer.
    PloS one, 2017, Volume: 12, Issue:5

    Epidemiological studies have shown obesity to be linked with poorer outcomes in breast cancer patients. The molecular mechanisms responsible for the increased risk of invasive/metastatic disease with obesity are complex, but may include elevated levels of adipokines such as leptin. Using physiological levels of leptin found in obesity in a novel chronic in vitro treatment model (≤200 ng/ml for 14 days), we confirmed the occurrence of leptin-mediated changes in growth, apoptosis and metastatic behavior, and gene expression changes representing epithelial-to-mesenchymal transition (EMT) and a cancer stem cell (CSC) like phenotype in breast epithelial and cancer cell lines (MCF10A, MCF10AT1, MCF7 and MDA-MB-231). Further, we have discovered that these effects were accompanied by increased expression of TGFB1, and could be significantly reduced by co-treatment with neutralizing antibody against TGFB1, indicating that the induction of these characteristics was mediated via TGFB1. Occurring in both MCF7 and MCF10AT1 cells, it suggests these actions of leptin to be independent of estrogen receptor status. By linking leptin signalling to the established TGFB1 pathway of metastasis / EMT, this study gives a direct mechanism by which leptin can contribute to the poorer outcomes of obese cancer patients. Inhibitors of TGFB1 are in currently in phase III clinical trials in other malignancies, thus identifying the connection between leptin and TGFB1 will open new therapeutic opportunities for improving outcomes for obese breast cancer patients.

    Topics: Apoptosis; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Epithelial-Mesenchymal Transition; Female; Humans; Leptin; MCF-7 Cells; Neoplastic Stem Cells; Obesity; Signal Transduction; Transforming Growth Factor beta1

2017
Leptin induces CREB-dependent aromatase activation through COX-2 expression in breast cancer cells.
    Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2017, Volume: 106, Issue:Pt A

    Leptin plays a key role in the control of adipocyte formation, as well as in the associated regulation of energy intake and expenditure. The goal of this study was to determine if leptin-induced aromatase enhances estrogen production and induces tumor cell growth stimulation. To this end, breast cancer cells were incubated with leptin in the absence or presence of inhibitor pretreatment, and changes in aromatase and cyclooxygenase-2 (COX-2) expression were evaluated at the mRNA and protein levels. Transient transfection assays were performed to examine the aromatase and COX-2 gene promoter activities and immunoblot analysis was used to examine protein expression. Leptin induced aromatase expression, estradiol production, and promoter activity in breast cancer cells. Protein levels of phospho-STAT3, PKA, Akt, ERK, and JNK were increased by leptin. Leptin also significantly increased cAMP levels, cAMP response element (CRE) activation, and CREB phosphorylation. In addition, leptin induced COX-2 expression, promoter activity, and increased the production of prostaglandin E

    Topics: Aromatase; Breast Neoplasms; Cell Proliferation; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 2; Dinoprostone; Estrogens; Female; Humans; Leptin; MCF-7 Cells; Phosphorylation; Promoter Regions, Genetic

2017
Leptin promotes the migration and invasion of breast cancer cells by upregulating ACAT2.
    Cellular oncology (Dordrecht), 2017, Volume: 40, Issue:6

    Previously, it has been shown that obesity may be considered as a risk factor for breast cancer in postmenopausal women. Leptin, a hormone whose level is elevated in obesity, has been suggested to be involved in the development of breast cancer, and univariate survival analyses have shown that over-expression of ACAT2, an enzyme that is involved in the production of cholesteryl esters, may be associated with a poor prognosis. Here, we aimed to investigate the effect of leptin on the proliferation, migration and invasion of breast cancer cells, as well as to elucidate its underlying mode of action.. Gene expression changes in leptin treated breast cancer-derived MCF-7, T47D and BT474 cells were assessed using PCR array, qRT-PCR and Western blot analyses. The expression patterns of Ob-R (leptin receptor) and ACAT2 in breast cancer cells and primary breast cancer tissue samples were analyzed using immunofluorescence and immunohistochemistry, respectively. Leptin-induced proliferation of breast cancer cells was assessed using a CCK8 assay, and scratch wound and Transwell assays were used to assess breast cancer cell invasion and migration.. We found that, among the genes tested, ACAT2 expression exhibited the most significant changes in the leptin treated cells. In addition, we found that inhibition of ACAT2 expression using pyripyropene A (PPPA) or siRNA-mediated gene silencing significantly decreased leptin-induced proliferation, migration and invasion of MCF-7 and T47D cells. Subsequent Western blot analyses strongly indicated that the PI3K/AKT/SREBP2 signaling pathway was involved in leptin-induced ACAT2 upregulation in both MCF-7 and T47D cells. Finally, through the analysis of primary breast cancer tissue samples we found that ACAT2 may affect cancer progression through activation of the Ob-R.. Our data indicate that leptin may enhance the proliferation, migration and invasion of breast cancer cells via ACAT2 up-regulation through the PI3K/AKT/SREBP2 signaling pathway. Therefore, the leptin/ACAT2 axis may represent an attractive therapeutic target for breast cancer, particularly in postmenopausal and/or obese women.

    Topics: Acetyl-CoA C-Acetyltransferase; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Survival; Female; Humans; In Vitro Techniques; Leptin; MCF-7 Cells; Receptors, Leptin; Signal Transduction

2017
Puberty: Early starters.
    Nature, 2017, 10-04, Volume: 550, Issue:7674

    Topics: Adolescent; Adult; Aging; Benzhydryl Compounds; Breast Neoplasms; Child; Disease Susceptibility; Female; Flame Retardants; Humans; Kisspeptins; Leptin; Male; Menarche; Obesity; Phenols; Puberty; Time Factors; Uterine Neoplasms

2017
Biomarkers of inflammation and breast cancer risk: a case-control study nested in the EPIC-Varese cohort.
    Scientific reports, 2017, 10-05, Volume: 7, Issue:1

    Breast cancer (BC) is the leading cause of cancer death in women. Adipokines, and other inflammation molecules linked to adiposity, are suspected to be involved in breast carcinogenesis, however prospective findings are inconclusive. In a prospective nested case-control study within the EPIC-Varese cohort, we used conditional logistic regression to estimate rate ratios (RRs) for BC, with 95% confidence intervals (CI), in relation to plasma levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6, leptin, and adiponectin, controlling for BC risk factors. After a median 14.9 years, 351 BC cases were identified and matched to 351 controls. No marker was significantly associated with BC risk overall. Significant interactions between menopausal status and CRP, leptin, and adiponectin were found. Among postmenopausal women, high CRP was significantly associated with increased BC risk, and high adiponectin with significantly reduced risk. Among premenopausal women, high TNF-α was associated with significantly increased risk, and high leptin with reduced risk; interleukin-6 was associated with increased risk only in a continuous model. These findings constitute further evidence that inflammation plays a role in breast cancer. Interventions to lower CRP, TNF-α, and interleukin-6 and increase adiponectin levels may contribute to preventing BC.

    Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Female; Genetic Association Studies; Humans; Inflammation; Interleukin-6; Leptin; Middle Aged; Postmenopause; Risk Factors; Tumor Necrosis Factor-alpha

2017
Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells.
    Oncology reports, 2017, Volume: 38, Issue:5

    NADPH oxidase (NOX) complexes (a family of seven isoforms) drive cellular ROS production in patho-logical processes such as cancer. NOX-driven ROS production is involved in cell mechanisms from signalling to oxidative stress. Leptin, an adipokine overexpressed in obese patients, has been investigated in studies on breast carcinogenesis, but its effects on oxidative stress remain largely unexplored, especially in breast cancer. The study used three human mammary epithelial cell models presenting different neoplastic status (healthy primary HMECs, neoplastic MCF-7 cells and neoplastic MDA-MB-231 cells) to determine the effects of leptin on short-term ROS production and to characterize the enzymes involved. All three cell models significantly expressed NADPH oxidase isoform 5 (NOX5) in our culture conditions. All models showed induced ROS production regardless of leptin concentration (10 ng/ml mimicking good health, 100 ng/ml mimicking obesity). Cell treatment with either siRNA against NOX5, NOX inhibitor DPI or a calcium channel blocker (verapamil) confirmed the putative involvement of the NOX5 isoenzyme in ROS production. Moreover, cell treatments suppressed ROS production under leptin at both concentrations. Neoplastic cells appeared unable to downregulate NOX5 mRNA expression under leptin. Leptin emerged as a potential activator of ROS production in human epithelial mammary cells, where the ROS production was apparently linked to NOX5 activation. This novel finding could shed light on the potential role of obesity-associated hyperleptinemia in mammary cells via the activation of NOX enzymes.

    Topics: Breast Neoplasms; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mammary Glands, Human; MCF-7 Cells; NADPH Oxidase 5; Oxidative Stress; Reactive Oxygen Species; RNA, Small Interfering; Verapamil

2017
Acetyl-CoA Carboxylase 1-Dependent Protein Acetylation Controls Breast Cancer Metastasis and Recurrence.
    Cell metabolism, 2017, Dec-05, Volume: 26, Issue:6

    Breast tumor recurrence and metastasis represent the main causes of cancer-related death in women, and treatments are still lacking. Here, we define the lipogenic enzyme acetyl-CoA carboxylase (ACC) 1 as a key player in breast cancer metastasis. ACC1 phosphorylation was increased in invading cells both in murine and human breast cancer, serving as a point of convergence for leptin and transforming growth factor (TGF) β signaling. ACC1 phosphorylation was mediated by TGFβ-activated kinase (TAK) 1, and ACC1 inhibition was indispensable for the elevation of cellular acetyl-CoA, the subsequent increase in Smad2 transcription factor acetylation and activation, and ultimately epithelial-mesenchymal transition and metastasis induction. ACC1 deficiency worsened tumor recurrence upon primary tumor resection in mice, and ACC1 phosphorylation levels correlated with metastatic potential in breast and lung cancer patients. Given the demonstrated effectiveness of anti-leptin receptor antibody treatment in halting ACC1-dependent tumor invasiveness, our work defines a "metabolocentric" approach in metastatic breast cancer therapy.

    Topics: Acetyl-CoA Carboxylase; Acetylation; Animals; Breast Neoplasms; Disease Models, Animal; Female; HEK293 Cells; Humans; Leptin; Lung Neoplasms; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Metastasis; Neoplasm Recurrence, Local; Tissue Array Analysis

2017
Immunohistochemical staining of leptin is associated with grade, stage, lymph node involvement, recurrence, and hormone receptor phenotypes in breast cancer.
    BMC women's health, 2017, Nov-09, Volume: 17, Issue:1

    Obesity is part of the established risk factors for breast cancer (BC) in postmenopausal females. Circulating leptin increases in parallel with the increase of body weight and fat reservoir.. This research investigated the link between leptin phenotype and the clinicopathological factors in BC. A large set of breast cancer cases (449), and 27 non-cancerous tissue samples of breast were employed for leptin expression recognition using immunohistochemistry staining.. Cytoplasmic immunohistochemical staining of leptin was recognized in 376 (83.7%) and 25 (92.6%) of BC and control cases respectively. Leptin immunostaining were significantly associated with age, histotypes, grade, stage, lymph node involvement, tumor recurrence, hormone receptor phenotypes, ER and HER2 expressions, and p-values were (P = 0.0233), (P = 0.0001), (P = 0.050), (P = 0.0291), (P = 0.0300), (P = 0.0023), (P = 0.0021), (P = 0.0279) respectively. Reasonable proportion of cases with low staining score was more prevalent in all subgroups of clinicopathological parameters except ER- PR+ HER2- hormone receptor phenotype and mucinous carcinoma which showed high level of leptin immunoreactivity. Tumor recurrence is less prevailing in high score leptin immunostaining cases. Furthermore, Log Rank (Mantel-Cox) test findings revealed considerably different survival distributions were observed for the different categories of leptin immunostaining scores (P = 0.032). Negative leptin immunostaining is related to poor survival.. Our preliminary findings support leptin clinical value in confirming BC diagnosis as well as prognosis. These results suggest that leptin molecule is an important biomarker that could identify type, grade, stage, lymph node involvement, relapse and prognosis in breast cancer.

    Topics: Breast Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymph Nodes; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Staining and Labeling

2017
Expression of AdipoR1 and AdipoR2 Receptors as Leptin-Breast Cancer Regulation Mechanisms.
    Disease markers, 2017, Volume: 2017

    The development of breast cancer is influenced by the adipose tissue through the proteins leptin and adiponectin. However, there is little research concerning AdipoR1 and AdipoR2 receptors and the influence of leptin over them. The objective of this work was to analyze the expression of AdipoR1 and AdipoR2, modulated by differential concentrations of leptin in an obesity model (10 ng/mL, 100 ng/mL, and 1000 ng/mL) associated with breast cancer in MCF-7 and HCC1937 cell lines. Each cell line was characterized through immunohistochemistry, and the expression of AdipoR1 and AdipoR2 was analyzed by PCR in real time using TaqMan® probes. Leptin induced an increase in cell population of MCF-7 (23.8%, 10 ng/mL, 48 h) and HCC1937 (17.24%, 1000 ng/mL, 72 h). In MCF-7, the expression of AdipoR1 decreased (3.81%, 1000 ng/mL) and the expression of AdipoR2 increased by 13.74 times (10 ng/mL) with regard to the control. In HCC1937, the expression of AdipoR1 decreased by 86.28% (10 ng/mL), as well as the expression of AdipoR2 (50.3%, 100 ng/mL). In regard to the results obtained, it could be concluded that leptin has an effect over the expression of AdipoR1 and AdipoR2 mRNA.

    Topics: Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Receptors, Adiponectin

2017
Insulin use, adipokine profiles and breast cancer prognosis.
    Cytokine, 2017, Volume: 89

    Type-2 diabetes mellitus (T2DM) and breast cancer (BC) share common cytokine signaling changes resultant from adipose tissue dysfunction. This modified adipokine signaling was shown to be directly associated with changes in the body mass index (BMI) and diet and it is expected to also be influenced by T2DM pharmacotherapy. We evaluated the relationship between pre-existing diabetes treatment, circulating adipokine levels at cancer diagnosis, and long-term outcomes.. Insulin use is associated with elevated leptin, CRP, TNFα, and lower C-peptide and also linked to poor BC outcomes. More research is needed to verify these findings; however, we are among the first to correlate pharmacotherapy use, measures of adipose tissue dysfunction and cancer outcomes.

    Topics: Adult; Aged; Breast Neoplasms; C-Peptide; C-Reactive Protein; Cytokines; Diabetes Mellitus, Type 2; Disease-Free Survival; Female; Humans; Insulin; Leptin; Middle Aged; Survival Rate

2017
Subcellular localization of leptin and leptin receptor in breast cancer detected in an electron microscopic study.
    Biochemical and biophysical research communications, 2017, Jan-22, Volume: 482, Issue:4

    Leptin (LEP) and leptin receptor (LEPR) have long been found associated with breast cancer. So far no high-resolution method such as electron microscopy has been used to investigate the subcellular localization of leptin and leptin receptor in breast cancer. We collected cancer and non-cancer breast tissues from 51 women with invasive ductal breast cancer. Leptin and leptin receptor in the tissues were estimated using immunohistochemistry (IHC). LEP and LEPR were localized at subcellular level by immunocytochemistry (ICC) using ultra-fine gold particle conjugated antibody, and visualized with transmission electron microscopy (TEM). IHC showed high presence of LEP and LEPR in 65% and 67% respectively of the breast cancer samples, 100% and 0% respectively of the adipose tissue samples, and no high presence in the non-cancer breast tissue samples. On TEM views both LEP and LEPR were found highly concentrated within the nucleus of the cancer cells, indicating that nucleus is the principal seat of action. However, presence of high concentration of LEP does not necessarily prove its over-expression, as often concluded, because LEP could be internalized from outside by LEPR in the cells. In contrast, LEPR is definitely over-expressed in the ductal breast cancer cells. Therefore, we hypothesize that over-expression of LEPR, rather than that of LEP has a fundamental role in breast carcinogenesis in particular, and probably for LEP-LEPR associated tumors in general.

    Topics: Adult; Body Mass Index; Breast Neoplasms; Carcinogenesis; Carcinoma, Ductal, Breast; Cell Nucleus; Female; Humans; Immunohistochemistry; Leptin; Microscopy, Electron, Transmission; Middle Aged; Protein Binding; Receptors, Leptin

2017
Suberoylanilide hydroxamic acid-induced specific epigenetic regulation controls Leptin-induced proliferation of breast cancer cell lines.
    Oncotarget, 2017, 01-10, Volume: 8, Issue:2

    Breast cancer is one of the most common malignancies among women in the world, investigating the characteristics and special transduction pathways is important for better understanding breast development and tumorigenesis. Leptin, a peptide hormone secreted from white adipocytes, may be an independent risk factor for breast cancer.Here, we treated suberoylanilide hydroxamic acid (SAHA) on Leptin-induced cell proliferation and invasion in the estrogen-receptor-positive breast cancer cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. Low concentrations of Leptin (0.625 nM) significantly stimulated breast cancer cell growth, enhanced cell viability, minimized apoptosis, and increased cell cycle transition. In contrast, SAHA (5 μM) treatment had reverse effects. Wound healing assay showed that, in MCF-7 and MDA-MB-231 cell line, cell migrating stimulated by Leptin was significantly repressed with SAHA treatment. Moreover, cell cycle real-time PCR array and proteome profiler antibody array confirmed that Leptin and SAHA treatment significantly changed the expressions of factors associated with cell cycle regulation and apoptosis including p53 and p21WAF1/CIP1.In DNA-ChIP analysis, we found that acetylation levels binding with p21WAF1/CIP1 promoters are regulated in a manner specific to histone type, lysine residue and selective promoter regions. SAHA significantly up-regulated the acetylation levels of AcH3-k14 and AcH3-k27 in MCF-7 cells, whereas Leptin repressed the modification. In addition, SAHA or Leptin had no significant effects on the AcH4 acetylation binding with any regions of p21WAF1/CIP1 promoter. In MDA-MB-231 cells, SAHA alone or in combination with Leptin significantly increased acetylation levels of Ach3-k27, Ach3-k18 and Ach4-k5 residues. However, no clear change was found with Leptin alone at all. Overall, our data will inform future studies to elucidate the mechanisms of p21WAF1/CIP1 transcriptional regulation, and the functional roles of p21WAF1/CIP1 in breast cancer tumorigenesis.

    Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Leptin; Promoter Regions, Genetic; Vorinostat

2017
Disease Subtype-Independent Biomarkers of Breast Cancer Chemoprevention by the Ayurvedic Medicine Phytochemical Withaferin A.
    Journal of the National Cancer Institute, 2017, Volume: 109, Issue:6

    A nontoxic chemopreventive intervention efficacious against different subtypes of breast cancer is still a clinically unmet need. The present study was undertaken to determine the efficacy of an Ayurvedic medicine phytochemical (Withaferin A, [WA]) for chemoprevention of breast cancer and to elucidate its mode of action.. Chemopreventive efficacy of WA (4 and 8 mg/kg body weight) was determined using a rat model of breast cancer induced by N-methyl-N-nitrosourea (MNU; n = 14 for control group, n = 15 for 4 mg/kg group, and n = 18 for 8 mg/kg group). The mechanisms underlying breast cancer chemoprevention by WA were elucidated by immunoblotting, biochemical assays, immunohistochemistry, and cytokine profiling using plasma and tumors from the MNU-rat (n = 8-12 for control group, n = 7-11 for 4 mg/kg group, and n = 8-12 for 8 mg/kg group) and/or mouse mammary tumor virus-neu (MMTV-neu) models (n = 4-11 for control group and n = 4-21 for 4 mg/kg group). Inhibitory effect of WA on exit from mitosis and leptin-induced oncogenic signaling was determined using MCF-7 and/or MDA-MB-231 cells. All statistical tests were two-sided.. Incidence, multiplicity, and burden of breast cancer in rats were decreased by WA administration. For example, the tumor weight in the 8 mg/kg group was lower by about 68% compared with controls (8 mg/kg vs control, mean = 2.76 vs 8.59, difference = -5.83, 95% confidence interval of difference = -9.89 to -1.76, P = .004). Mitotic arrest and apoptosis induction were some common determinants of breast cancer chemoprevention by WA in the MNU-rat and MMTV-neu models. Cytokine profiling showed suppression of plasma leptin levels by WA in rats. WA inhibited leptin-induced oncogenic signaling in cultured breast cancer cells.. WA is a promising chemopreventative phytochemical with the ability to inhibit at least two different subtypes of breast cancer.

    Topics: 8-Hydroxy-2'-Deoxyguanosine; Acetyl Coenzyme A; Aldehyde Dehydrogenase 1 Family; Animals; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Cell Cycle; Cytokines; Deoxyguanosine; Electron Transport Complex III; Female; Forkhead Transcription Factors; Humans; Ki-67 Antigen; Lactic Acid; Leptin; Malates; Mammary Neoplasms, Experimental; Mammary Tumor Virus, Mouse; MCF-7 Cells; Methylnitrosourea; Mice; Mitosis; Mitotic Index; Rats; Receptors, Estrogen; Retinal Dehydrogenase; Retroviridae Infections; Signal Transduction; Tumor Burden; Tumor Virus Infections; Withanolides

2017
Circulating leptin, soluble leptin receptor, free leptin index, visfatin and selected leptin and leptin receptor gene polymorphisms in sporadic breast cancer.
    Endocrine journal, 2017, Apr-29, Volume: 64, Issue:4

    Leptin and visfatin are implicated in breast cancer risk but studies accounting for bioavailability of leptin are sparse. Reports on the association of leptin gene (LEP) and leptin receptor gene (LEPR) polymorphisms with breast cancer are also inconsistent. Only a very few studies have examined biochemical and genetic variables concomitantly in the same cohort. A matched pairs study was carried out to ascertain whether plasma leptin, soluble leptin receptor, free leptin index (leptin/soluble leptin receptor), serum visfatin and selected LEP and LEPR polymorphisms are risk factors for sporadic breast cancer. Newly diagnosed sporadic breast cancer patients (N=80) were matched for age, body mass index (BMI) and menopausal status with healthy controls. Plasma leptin, soluble leptin receptor and serum visfatin were measured by enzyme-immunoassay. LEP -2548 A/G and LEPR K109R, LEPR Q223R polymorphisms were determined by genotyping. Leptin (p=0.0234), leptin/BMI (p=0.0468), free leptin index (p<0.0001) and visfatin (p=0.0002) were significantly higher and soluble leptin receptor (p<0.0001) was significantly lower in patients. LEPR gene K109R A/G polymorphism increased breast cancer risk (odds ratio: 4.125). Multivariate analysis confirmed that leptin, soluble leptin receptor, free leptin index and G109 (R109) allele of the LEPR gene K109R polymorphism are risk factors for breast cancer. When stratified by menopausal status free leptin index and soluble leptin receptor remained as risk factors irrespective of menopausal status while LEPR gene K109R A/G polymorphism remained as a risk factor only in the postmenopausal group.

    Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Cytokines; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Menopause; Middle Aged; Nicotinamide Phosphoribosyltransferase; Polymorphism, Single Nucleotide; Receptors, Leptin; Young Adult

2017
Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.
    Oncotarget, 2016, Jan-12, Volume: 7, Issue:2

    Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression.

    Topics: Blotting, Western; Breast Neoplasms; Cell Communication; Cell Line, Tumor; Cells, Cultured; Culture Media, Conditioned; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Kaplan-Meier Estimate; Leptin; MCF-7 Cells; Neoplastic Stem Cells; Oligonucleotide Array Sequence Analysis; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Spheroids, Cellular; Stromal Cells; Tumor Microenvironment

2016
The Effects of Adjuvant Endocrine Treatment on Serum Leptin, Serum Adiponectin and Body Composition in Patients with Breast Cancer: The Izmir Oncology Group (IZOG) Study.
    Chemotherapy, 2016, Volume: 61, Issue:2

    A limited number of studies have been conducted on the effects of hormonal therapy with tamoxifen (TMX) or aromatase inhibitors (AIs) on plasma levels of leptin and adiponectin, as well as body composition in breast cancer (BC) patients. Therefore, we aimed to analyze the relationship between adipocytokines and body composition as well as the effects of TMX and AIs on plasma adiponectin, leptin, leptin/adiponectin ratio (LAR) and body composition.. Patients were treated with either TMX or AI according to their menopausal status after adjuvant radiotherapy. Changes in body composition and serum leptin and adiponectin levels were evaluated. We recorded the type of hormonal therapy, BMI, waist/hip ratio (WHR), leptin and adiponectin levels at study entry, and after 6 and 12 months.. From baseline to the 6- and 12-month follow-ups, there were statistically significant increases in WHR (p = 0.003), fat mass (p = 0.041), and serum leptin (p < 0.001) and adiponectin levels (p < 0.001). The changes in body composition and serum leptin and adiponectin levels were similar in TMX and AI groups. A statistically significant decrease was found in total body water and LAR (p < 0.001). Although weight and body fat percentage increased, such increases were not statistically significant. A positive correlation was found between baseline BMI and serum leptin levels. This correlation was maintained at 6 and 12 months. The negative correlation found between serum adiponectin levels at baseline and baseline BMI did not last throughout the study.. In this study, increased leptin and adiponectin levels and a decreased LAR were found in both AI and TMX groups. These changes might have occurred through both mechanisms of hormonal therapy and body composition changes. Therefore, AIs and TMX may exert their protective effects for BC patients by decreasing LAR rather than affecting leptin or adiponectin alone.

    Topics: Adiponectin; Adult; Anastrozole; Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Body Composition; Body Mass Index; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Leptin; Letrozole; Middle Aged; Nitriles; Tamoxifen; Triazoles

2016
Systemic Correlates of White Adipose Tissue Inflammation in Early-Stage Breast Cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2016, 05-01, Volume: 22, Issue:9

    Obesity, insulin resistance, and elevated levels of circulating proinflammatory mediators are associated with poorer prognosis in early-stage breast cancer. To investigate whether white adipose tissue (WAT) inflammation represents a potential unifying mechanism, we examined the relationship between breast WAT inflammation and the metabolic syndrome and its prognostic importance.. WAT inflammation was defined by the presence of dead/dying adipocytes surrounded by macrophages forming crown-like structures (CLS) of the breast. Two independent groups were examined in cross-sectional (cohort 1) and retrospective (cohort 2) studies. Cohort 1 included 100 women undergoing mastectomy for breast cancer risk reduction (n = 10) or treatment (n = 90). Metabolic syndrome-associated circulating factors were compared by CLS-B status. The association between CLS of the breast and the metabolic syndrome was validated in cohort 2, which included 127 women who developed metastatic breast cancer. Distant recurrence-free survival (dRFS) was compared by CLS-B status.. In cohorts 1 and 2, breast WAT inflammation was detected in 52 of 100 (52%) and 52 of 127 (41%) patients, respectively. Patients with breast WAT inflammation had elevated insulin, glucose, leptin, triglycerides, C-reactive protein, and IL6 and lower high-density lipoprotein cholesterol and adiponectin (P < 0.05) in cohort 1. In cohort 2, breast WAT inflammation was associated with hyperlipidemia, hypertension, and diabetes (P < 0.05). Compared with patients without breast WAT inflammation, the adjusted HR for dRFS was 1.83 (95% CI, 1.07-3.13) for patients with inflammation.. WAT inflammation, a clinically occult process, helps to explain the relationship between metabolic syndrome and worse breast cancer prognosis. Clin Cancer Res; 22(9); 2283-9. ©2015 AACR.

    Topics: Adipocytes; Adipose Tissue, White; Adult; Aged; Breast; Breast Neoplasms; C-Reactive Protein; Cross-Sectional Studies; Female; Glucose; Humans; Inflammation; Insulin; Interleukin-6; Leptin; Macrophages; Metabolic Syndrome; Middle Aged; Obesity; Retrospective Studies; Triglycerides

2016
Leptin regulates energy metabolism in MCF-7 breast cancer cells.
    The international journal of biochemistry & cell biology, 2016, Volume: 72

    Obesity is known to be a poorer prognosis factor for breast cancer in postmenopausal women. Among the diverse endocrine factors associated to obesity, leptin has received special attention since it promotes breast cancer cell growth and invasiveness, processes which force cells to adapt their metabolism to satisfy the increased demands of energy and biosynthetic intermediates. Taking this into account, our aim was to explore the effects of leptin in the metabolism of MCF-7 breast cancer cells. Polarographic analysis revealed that leptin increased oxygen consumption rate and cellular ATP levels were more dependent on mitochondrial oxidative metabolism in leptin-treated cells compared to the more glycolytic control cells. Experiments with selective inhibitors of glycolysis (2-DG), fatty acid oxidation (etomoxir) or aminoacid deprivation showed that ATP levels were more reliant on fatty acid oxidation. In agreement, levels of key proteins involved in lipid catabolism (FAT/CD36, CPT1, PPARα) and phosphorylation of the energy sensor AMPK were increased by leptin. Regarding glucose, cellular uptake was not affected by leptin, but lactate release was deeply repressed. Analysis of pyruvate dehydrogenase (PDH), lactate dehydrogenase (LDH) and pyruvate carboxylase (PC) together with the pentose-phosphate pathway enzyme glucose-6 phosphate dehydrogenase (G6PDH) revealed that leptin favors the use of glucose for biosynthesis. These results point towards a role of leptin in metabolic reprogramming, consisting of an enhanced use of glucose for biosynthesis and lipids for energy production. This metabolic adaptations induced by leptin may provide benefits for MCF-7 growth and give support to the reverse Warburg effect described in breast cancer.

    Topics: Adenosine Triphosphate; Breast Neoplasms; Cell Proliferation; Energy Metabolism; Glucose; Humans; Leptin; Lipid Metabolism; MCF-7 Cells; Mitochondria

2016
Effect of low or high glycemic load diets on experimentally induced mammary carcinogenesis in rats.
    Molecular nutrition & food research, 2016, Volume: 60, Issue:6

    High glycemic load diets have been associated with increased breast cancer risk in population-based studies, but the evidence is mixed. This investigation determined whether diets differing in glycemic load affected the carcinogenic process using a preclinical model.. Human diets, formulated to differ 2-fold in glycemic load, were evaluated in the 1-methyl-nitrosourea-induced (37.5 mg/kg) mammary carcinogenesis model. Cancer incidence (23.3 versus 50.0%, p = 0.032), multiplicity, (0.40 versus 1.03, p = 0.030) and burden, (0.62 versus 1.19 g/rat, p = 0.037) were reduced in the low versus high glycemic load diets, respectively. However, the low glycemic protective effect was attenuated when two purified diets that differed in resistant starch and simulated the glycemic effects of the human diets were fed. Protection was associated with alterations in markers of cell growth regulation.. Our findings show that human low or high glycemic load dietary patterns differentially affect the carcinogenic response in a nondiabetic rodent model for breast cancer. However, factors that are associated with these patterns, in addition to dietary carbohydrate availability, appear to account for the differences observed.

    Topics: Adiponectin; Animals; Blood Glucose; Breast Neoplasms; Diet; Dietary Carbohydrates; Disease Models, Animal; Female; Glycemic Index; Glycemic Load; Insulin; Leptin; Nitrosourea Compounds; Principal Component Analysis; Rats; Rats, Sprague-Dawley

2016
Hyperresistinemia and metabolic dysregulation: a risky crosstalk in obese breast cancer.
    Endocrine, 2016, Volume: 53, Issue:2

    Breast cancer is the most common malignancy among women worldwide. There is extensive literature on the relationship between body weight and breast cancer risk but some doubts still remain about the role of adipokines per se, the role of insulin and glucose regardless of obesity, as well as the crosstalk between these players. Thus, in this study, we intend to determine the relation between body mass index (BMI), glycaemia, insulinemia, insulin-resistance, blood adipokine levels and tumour characteristics in a Portuguese group of pre- and postmenopausal overweight/obese women with breast cancer. We evaluated clinical and biochemical data in 154 participants, divided in 4 groups: (1) control with BMI <25 kg/m(2), n = 29 (CT); (2) control with BMI >25 kg/m(2), n = 48 (CTOb); (3) breast cancer with BMI <25 kg/m(2), n = 30 (BC); and (4) breast cancer with BMI >25 kg/m(2), n = 47 (BCOb). In women with breast cancer, we also performed tumour characterization. We found that BCOb present increased fasting blood glucose, insulin, resistin and monocyte chemoattractant protein 1, insulin resistance and more aggressive tumours. Notably, this profile is not correlated with BMI, proposing the involvement of other processes than adiposity. Altogether, our results suggest that glucose dysmetabolism, insulin resistance and changes in adipokine secretion, in particular resistin, may be involved in the development and progression of breast cancer in overweight/obese pre- and postmenopausal women.

    Topics: Adiponectin; Adult; Aged; Blood Glucose; Breast Neoplasms; Female; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Resistin

2016
Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.
    Scientific reports, 2016, Feb-22, Volume: 6

    Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.

    Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cancer-Associated Fibroblasts; Carcinogenesis; Cell Communication; Cell Line, Tumor; Culture Media, Conditioned; Female; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Leptin; MCF-7 Cells; Mice, Nude; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Xenograft Model Antitumor Assays

2016
Leptin promotes breast cancer cell migration and invasion via IL-18 expression and secretion.
    International journal of oncology, 2016, Volume: 48, Issue:6

    In recent years, crosstalk between tumor microenvironment and cancer cells have received increasing attention. Accumulating research data suggests that leptin, a key adipokine secreted from adipocytes, plays important roles in breast cancer development. In our study, the effects of leptin on polarization of tumor-associated macrophages (TAMs) and promotion of the invasiveness of tumor cells were investigated. THP1 cells were used to differentiate M2 polarization macrophages. After stimulated by leptin, we established a co-culture system of tumor cells and macrophages to evaluate the function of leptin-induced macrophages in the migration and invasion of breast cancer cells. The gene and protein expressions were analyzed and the underlying mechanisms were evaluated. Moreover, pathological human specimens, and xenografts in nude mice, were detected to strengthen the in vitro results. Leptin elevated the expression of an array of cytokines in TAMs, IL-18 was the most increased, with an activation of the NF-κB/NF-κB1 signalling pathway. Additionally, after treated with leptin, TAMs significantly promoted the migration and invasion of breast cancer cells. However, these effects of leptin were abolished by the co-incubation of Bay11‑7082, a pharmacological NF-κB inhibitor. Leptin also directly stimulated IL-18 expression in breast cancer cells, which, differently, was via the PI3K/AKT-ATF-2 signaling pathway. In vivo studies showed that malignant breast carcinoma exhibited strong higher expression of Leptin, IL-8, and TAMs markers. Xenograft tumor-bearing mouse models showed that leptin significantly increased tumor volume, enhanced lung metastases, and increased expression of IL-8 and TAM markers, which were abolished by depletion of macrophages by clophosome-clodronate liposomes (CCL). Leptin could induce IL-18 expression both in TAMs and breast cancer cells. Leptin-induced IL-18 expression was regulated via NF-κB/NF-κB1 signaling in TAMs, while via PI3K-AKT/ATF-2 signaling in breast cancer cells, which, eventually, lead to invasion and metastasis of breast cancer cells.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cells, Cultured; Coculture Techniques; Female; Humans; Interleukin-18; Leptin; Macrophages; MCF-7 Cells; Mice; Neoplasm Invasiveness; Neoplasm Transplantation; Signal Transduction; Tumor Microenvironment

2016
Low expression of leptin and its association with breast cancer: A transcriptomic study.
    Oncology reports, 2016, Volume: 36, Issue:1

    The incidence of breast cancer is alarmingly increasing worldwide and also among Saudi women. Obesity is linked with an increased cancer risk and studies have also revealed that leptin may be involved in breast tumorigenesis particularly among obese women. Numerous transcriptomic studies have been carried out worldwide; however, molecular studies among breast cancer patients of diverse ethnic groups from the Arabian Peninsula are scarce. In the present study, whole transcriptome analysis of 45 surgically resected breast tumors from Saudi Arabian female patients was carried out. Expression data were analyzed, and molecular networks and canonical pathways were identified. We identified 1,159 differentially expressed genes using p-value with a false discovery rate <0.05 and a fold-change >2 as a cut-off. Using ingenuity pathway analysis tool, we identified many canonical pathways that were implicated in breast cancer for the first time. Notably, along with other lipid metabolism molecules, leptin (LEP)was one of the most downregulated genes (fold cut-off, -7.03) with significant differences between the breast cancer and the control groups (p<0.0001) and was further confirmed in all the samples using qPCR. Transcriptomic profiling of breast cancer from a Saudi female population revealed downregulation of LEP. Molecular pathway analysis demonstrated the role of LEP and other associated molecules of the lipid metabolism pathway. Involvement of leptin and lipid metabolism in breast cancer was highlighted. The majority of cases presented were of late stage, stressing the need to educate individuals concerning early diagnostic testing and the life-style risk factors for breast cancer such as unhealthy diet and obesity.

    Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Leptin; Lipid Metabolism; Middle Aged; Receptors, Leptin; Saudi Arabia; Signal Transduction; Transcriptome

2016
Sam68 Mediates the Activation of Insulin and Leptin Signalling in Breast Cancer Cells.
    PloS one, 2016, Volume: 11, Issue:7

    Obesity is a well-known risk factor for breast cancer development in postmenopausal women. High insulin and leptin levels seem to have a role modulating the growth of these tumours. Sam68 is an RNA-binding protein with signalling functions that has been found to be overexpressed in breast cancer. Moreover, Sam68 may be recruited to insulin and leptin signalling pathways, mediating its effects on survival, growth and proliferation in different cellular types. We aimed to study the expression of Sam68 and its phosphorylation level upon insulin and leptin stimulation, and the role of Sam68 in the proliferative effect and signalling pathways that are activated by insulin or leptin in human breast adenocarcinoma cells. In the human breast adenocarcinoma cell lines MCF7, MDA-MB-231 and BT-474, Sam68 protein quantity and gene expression were increased upon leptin or insulin stimulation, as it was checked by qPCR and immunoblot. Moreover, both insulin and leptin stimulation promoted an increase in Sam68 tyrosine phosphorylation and negatively regulated its RNA binding capacity. siRNA was used to downregulate Sam68 expression, which resulted in lower proliferative effects of both insulin and leptin, as well as a lower activation of MAPK and PI3K pathways promoted by both hormones. These effects may be partly explained by the decrease in IRS-1 expression by down-regulation of Sam68. These results suggest the participation of Sam68 in both leptin and insulin receptor signaling in human breast cancer cells, mediating the trophic effects of these hormones in proliferation and cellular growth.

    Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins; Female; Humans; Insulin; Insulin Receptor Substrate Proteins; Leptin; Phosphorylation; RNA-Binding Proteins; Signal Transduction

2016
Serum resistin is inversely related to breast cancer risk in premenopausal women.
    Breast (Edinburgh, Scotland), 2016, Volume: 29

    Adipokines have been suggested as potential mediators linking obesity and breast cancer. Resistin is the least-studied adipokine with diverse findings regarding its association with disease development and progression. The present study aimed to determine resistin serum levels in breast cancer in relation to the histological type of disease and to investigate their association with breast cancer risk.. The study included 216 women, of which 163 were diagnosed with breast cancer (58 with IDC, 52 with DCIS and 53 with LN) and 53 were healthy. Serum levels of resistin, leptin and adiponectin were quantitatively determined in duplicates by ELISA. Differences in resistin levels among patient groups were evaluated with Kruskal-Wallis and Mann-Whitney tests. The association of resistin with breast cancer risk was evaluated by multiple logistic regression analysis.. Resistin levels varied between histological types of breast cancer (p = 0.044). Significant differences in serum resistin were observed in IDC patients compared to those with DCIS and to controls (p < 0.014 and p < 0.03, respectively). Decreased levels of resistin, adiponectin and leptin were observed in premenopausal patients. Resistin was associated with a reduced risk for ductal carcinoma only in premenopausal women (OR: 0.364, 95% CI: 0.154-0.862, p < 0.022).. Our findings indicate that resistin levels were inversely related to breast cancer risk in premenopausal women, supporting a protective role of resistin for these patients. Further advances in adipokine research may lead to tangible benefits for overweight/obese women at an increased risk for breast cancer.

    Topics: Adiponectin; Adult; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Logistic Models; Middle Aged; Premenopause; Resistin; Risk Factors; Statistics, Nonparametric

2016
Leptin promotes migration and invasion of breast cancer cells by stimulating IL-8 production in M2 macrophages.
    Oncotarget, 2016, Oct-04, Volume: 7, Issue:40

    This study aims to investigate the mechanisms underlying leptin-mediated crosstalk between tumor-associated macrophages (M2 macrophages) and breast cancer cells. THP1 human leukemic monocytes were induced to differentiate into M2 macrophages by PMA (100 nM) and IL-4 (20 ng/mL). Quantitative RT-PCR and Western blot revealed that leptin (100 nM) significantly increased the expression of leptin receptor (ObR) in the M2 macrophages (P < 0.01) and stimulated interleukin (IL)-8 expression in the M2 macrophages, mouse macrophage cells RAW264.7, and primary mouse peritoneal macrophages in a dose- and time-dependent manner. Leptin-induced IL-8 production was sensitive to the ERK inhibitor PD980590 (10 μmol/L), p38 MAPK inhibitor SB203580 (20 μmol/L), and anti-ObR neutralizing antibody (4 μg/mL). Leptin (100 ng/mL) substantially increased the phosphorylation of p38 and ERK1/2. Thus, leptin may induce IL-8 production in M2 macrophages by interacting with ObR to activate the p38 and ERK signaling pathways. Scratch and transwell chamber assay showed that both recombinant IL-8 and leptin-induced M2 macrophage-derived IL-8 promoted the migration and invasion of human breast cancer cells MCF7 and MDA-MB-231 (All P < 0.01). In a nude mice xenograft model of breast cancer (n = 5 per group), injection of leptin (0.1 μg/g) dramatically increased tumor volume and mass, reduced survival, exacerbated pulmonary metastasis, and elevated IL-8 and Ki67 expression in the tumor tissue (All P < 0.05) compared with PBS injection. Depletion of mouse macrophage by Clophosome®-clodronate liposome and injection of anti-mouse IL-8 neutralizing antibodies in the xenograft tumor significantly attenuated those leptin-mediated stimulations (All P < 0.05). These findings indicate that leptin may promote tumor growth and metastasis by stimulating IL-8 production in tumor-associated macrophage.

    Topics: Animals; Antibodies, Blocking; Breast Neoplasms; Cell Differentiation; Cell Movement; Female; Humans; Interleukin-8; Leptin; Macrophages; MAP Kinase Signaling System; MCF-7 Cells; Mice; Mice, Nude; p38 Mitogen-Activated Protein Kinases; Phosphorylation; RAW 264.7 Cells; Receptors, Leptin; Tetradecanoylphorbol Acetate; Th1 Cells; Tumor Burden; Xenograft Model Antitumor Assays

2016
Leptin promotes epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2.
    Journal of experimental & clinical cancer research : CR, 2016, 10-21, Volume: 35, Issue:1

    Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. Leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in EMT. However, the potential mechanism remains unknown. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism.. With the assessment of EMT-associated marker expression in MCF-7, SK-BR-3, and MDA-MB-468 cells, the effect of leptin on breast cancer cells was analyzed. Besides, an array of pathway inhibitors as well as RNA interference targeting pyruvate kinase M2 (PKM2) were used to clarify the underlying mechanism of leptin-mediated EMT in vitro and in vivo.. The results demonstrated that leptin promoted breast cancer cells EMT, visibly activated the PI3K/AKT signaling pathway, and upregulated PKM2 expression. An antibody against the leptin receptor (anti-ObR) and the PI3K/AKT signaling pathway inhibitor LY294002 significantly abolished leptin-induced PKM2 expression and EMT-associated marker expression. SiRNA targeting PKM2 partially abolished leptin-induced migration, invasion, and EMT-associated marker expression. In vivo xenograft experiments indicated that RNA interference against PKM2 suppressed breast cancer growth and metastasis.. Our data suggest that leptin promotes EMT in breast cancer cells via the upregulation of PKM2 expression as well as activation of PI3K/AKT signaling pathway, and PKM2 might be one of the key points and potential targets for breast cancer therapy.

    Topics: Animals; Breast Neoplasms; Carrier Proteins; Cell Line, Tumor; Cell Movement; Chromones; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Membrane Proteins; Mice; Morpholines; Neoplasm Invasiveness; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Up-Regulation

2016
Sphingosine kinase 1 contributes to leptin-induced STAT3 phosphorylation through IL-6/gp130 transactivation in oestrogen receptor-negative breast cancer.
    Breast cancer research and treatment, 2015, Volume: 149, Issue:1

    Obesity is a known risk factor for breast cancer. We have recently identified that adipokine leptin regulates the expression of a proto-oncogenic enzyme sphingosine kinase 1 (SK1). Signal transducer and activator of transcription 3 (STAT3) has been linked to breast cancer progression and here we investigate the mechanism of leptin-induced STAT3 activation in ER-negative breast cancer. Gene and protein expression in human primary and secondary breast cancer tissues was analysed using quantitative real-time polymerase chain reaction (qRT-PCR) assay and immunofluorescence. Leptin-induced signalling was analysed in human ER-negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays. Gene expression and receptor signalling was modified using small interfering RNA and neutralising antibodies. In human ER-negative breast tumours and lymph node metastases, the expression of leptin receptor significantly correlated with SK1. In ER-negative breast cancer cells, SK1 knockdown led to a significant reduction in leptin-induced STAT3 phosphorylation. Knockdown of another known activator of STAT3 signalling, gp130 also resulted in a significant decrease in leptin-induced STAT3 phosphorylation. ELISA assay showed that leptin produces a significant amount of IL-6 in an SK1-dependent manner. IL-6 neutralising antibodies significantly reduced p-STAT3. Immunofluorescent staining of human primary and secondary breast tumours showed significant correlation between SK1 and IL-6 (P < 0.001), SK1 and p-STAT3 (P < 0.01) and IL-6 and p-STAT3 (P < 0.01). Our findings demonstrate that leptin-induced STAT3 is partially cross activated through SK1-mediated IL6 secretion and gp130 activation. Positive correlations in human tissues suggest the potential significance of this pathway in ER-negative breast cancer.

    Topics: Breast Neoplasms; Cell Line, Tumor; Cytokine Receptor gp130; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Interleukin-6; Leptin; Lymphatic Metastasis; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Receptors, Estrogen; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Transcriptional Activation

2015
The LEP G-2548A gene polymorphism is associated with age at menarche and breast cancer susceptibility.
    Gene, 2015, Feb-25, Volume: 557, Issue:2

    Leptin is an adipocytokine made by fat cells and plays a key role in proliferation, cell survival, migration and immune response. It has a powerful effect on the initiation of puberty and in determining age at menarche. The current study is the first investigation to examine the effect of G-2548A leptin gene polymorphism on the age at menarche and breast cancer susceptibility. This case-control study was performed on 203 patients with breast cancer and 171 healthy women. The leptin genotypes were determined using the PCR-RFLP method and age at menarche was obtained by questionnaires. There was a significant difference between the leptin G-2548A genotypes between case and control groups (P<0.05). AA genotype is significantly higher in patients compared to the controls. Furthermore, women carrying the AA genotype had a significantly younger age at menarche (12.47 years) than women with the AG (12.94 years) and GG (13.47 years) genotypes. Also, we found that the AA genotype frequency in women with age at menarche <13 years was higher than in women with age at menarche ≥13 years (OR: 3.4, 95% CI: 1.7-6.7, P: 0.001). In conclusion, the G-2548A leptin gene polymorphism has an important role in the onset of menarche and breast cancer susceptibility.

    Topics: Adolescent; Adult; Breast Neoplasms; Case-Control Studies; Child; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Leptin; Menarche; Middle Aged; Polymorphism, Single Nucleotide

2015
Synergy of leptin/STAT3 with HER2 receptor induces tamoxifen resistance in breast cancer cells through regulation of apoptosis-related genes.
    Cellular oncology (Dordrecht), 2015, Volume: 38, Issue:2

    Tamoxifen is a major treatment modality for estrogen receptor positive breast cancer, but the occurrence of resistance remains a problem. Recently, obesity-related leptin has been found to interfere with tamoxifen in breast cancer MCF-7 cells. In the present study we investigated the effect of leptin on three tamoxifen-treated breast cancer cell types (i.e., MDA-MB-231, MCF-7 and MCF-7/HER2).. The effect of tamoxifen/leptin treatment was evaluated using a MTT cell viability assay. mRNA expression was assessed by real time PCR and protein expression by Western blotting. WWOX, Survivin and BCL2 gene promoter activities were evaluated by chromatin immunoprecipitation.. Cell viability assays revealed that estrogen receptor negative MDA-MB-231 cells were resistant, that estrogen receptor positive MCF-7 cells were sensitive and that MCF-7/HER2 cells were relatively resistant to tamoxifen, while leptin co-administration 'rescued' MCF-7 and, especially, MCF-7/HER2 cells from the anti-proliferative effect of tamoxifen. The cell lines also exhibited a different phosphorylation status of STAT3, a transcription factor that is activated by the obesity related leptin receptor b (Ob-Rb). Most importantly, chromatin immunoprecipitation assays revealed differential STAT3 binding to the anti-apoptotic BCL2 and pro-apoptotic WWOX gene promoters in MCF-7 and MCF-7/HER2 cells, leading to concomitant modifications of its mRNA/protein expression levels, thus providing a selective advantage to HER2 over-expressing MCF-7/HER2 cells after treatment with tamoxifen and tamoxifen plus leptin.. Our study provides novel evidence indicating that synergy between the leptin/Ob-Rb/STAT3 signalling pathway and the HER2 receptor protects tamoxifen-treated HER2 over-expressing cells from the inhibitory effect of tamoxifen through differential regulation of apoptosis-related genes.

    Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Chromatin Immunoprecipitation; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2; Selective Estrogen Receptor Modulators; Signal Transduction; STAT3 Transcription Factor; Tamoxifen

2015
A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo.
    Journal of cellular and molecular medicine, 2015, Volume: 19, Issue:5

    The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I-III. Site I is crucial for the formation of an active leptin-leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage-dependent and -independent growth as well as the migration of ERα-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women.

    Topics: Amino Acid Sequence; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Humans; Immunoblotting; Leptin; MCF-7 Cells; Mitogen-Activated Protein Kinases; Oligopeptides; Phosphorylation; Polyethylene Glycols; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Tumor Burden; Xenograft Model Antitumor Assays

2015
Resistin, visfatin, adiponectin, and leptin: risk of breast cancer in pre- and postmenopausal saudi females and their possible diagnostic and predictive implications as novel biomarkers.
    Disease markers, 2015, Volume: 2015

    The mechanisms of obesity-induced breast carcinogenesis are not clear. One hypothesis is that high levels of adipokines could promote breast cancer (BC) development. The aim of this study was to investigate the correlation of resistin, visfatin, adiponectin, and leptin with BC risk in pre- and postmenopausal females. A total of 82 BC newly diagnosed and histologically confirmed patients and 68 age and BMI matched healthy controls were enrolled. Both groups were subdivided into post- and premenopausal subgroups. Resistin, visfatin, adiponectin, and leptin were measured by ELISA. There were significantly higher levels of leptin, resistin, and visfatin in postmenopausal BC patients than their respective controls. Only in postmenopausal subgroups, leptin, resistin, and visfatin levels were positively correlated with TNM staging, tumor size, lymph node (LN) metastasis, and histological grading. In postmenopausal females, multivariate logistic regression analysis revealed that adiponectin, leptin, visfatin, and resistin were risk factors for BC. Our results suggested that serum resistin, leptin, adiponectin, and visfatin levels as risk factors for postmenopausal BC may provide a potential link with clinicopathological features and are promising to be novel biomarkers for postmenopausal BC.

    Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Middle Aged; Nicotinamide Phosphoribosyltransferase; Postmenopause; Predictive Value of Tests; Resistin; Saudi Arabia

2015
Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression.
    Cancer research, 2015, Jun-01, Volume: 75, Issue:11

    Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.

    Topics: Animals; Breast Neoplasms; Carcinogenesis; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens; Histone-Lysine N-Methyltransferase; Humans; Leptin; Mammary Neoplasms, Animal; MCF-7 Cells; Mice; MicroRNAs; Neoplastic Stem Cells; Obesity; Rats; Receptors, Leptin; STAT3 Transcription Factor

2015
ObRb downregulation increases breast cancer cell sensitivity to tamoxifen.
    Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2015, Volume: 36, Issue:9

    Leptin is a potent adipokine that plays an important role in the progression of breast cancer and interferes with the action of tamoxifen. We investigated the molecular mechanism underlying the effect of leptin on tamoxifen resistance in breast cancer cells that express leptin receptor (ObRb), and evaluated the impact of ObRb suppression on tamoxifen treatment in MCF-7 and tamoxifen-resistant (TAM-R) cells. Leptin-induced signaling pathway activation was examined by qRT-PCR and Western blotting. Chromatin immunoprecipitation assays were performed to further examine the binding of estrogen receptor (ER) α on the promoter of cyclin D1 (CCND1) gene. The effects of combined ObRb knockdown and tamoxifen treatment were evaluated in MCF-7 and TAM-R cells. We found that the enhanced proliferation effects induced by leptin were related to extracellular-signal-regulated kinase (ERK) 1/2 and signal transducers and activators of transcription (STAT) 3 signaling pathway activation and CCND1 upregulation. Leptin enhanced CCND1 gene transcription by inducing the binding of ERα to the promoter of CCND1 gene. ObRb knockdown significantly enhanced the inhibitory effects of tamoxifen on TAM-R cell proliferation and survival. This study suggested that long-term endocrine therapy facilitates leptin and ObRb overexpression in breast cancer cells, which attenuates the inhibitory effect of tamoxifen by activating both the ERK1/2 and STAT3 signaling pathways and upregulating CCND1 gene expression. Combination therapy involving ObRb knockdown and tamoxifen treatment may be an alternative therapeutic option for tamoxifen-resistant breast cancer.

    Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Proliferation; Cyclin D1; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Receptors, Leptin; Signal Transduction; Tamoxifen

2015
The direct and indirect effects of corticosterone and primary adipose tissue on MCF7 breast cancer cell cycle progression.
    Hormone molecular biology and clinical investigation, 2015, Volume: 22, Issue:2

    Breast cancer is the second leading cause of cancer-related mortality in women. Glucocorticoids (GCs) have the potential to directly affect breast cancer or indirectly via changes to the tumor growth microenvironment a breast cancer is exposed to. The role of GCs in breast cancer progression by direct and indirect means are not fully understood.. To study the direct and indirect effects of GCs on breast cancer cell cycle regulation.. MCF7 breast cancer cells were incubated with increasing concentrations of corticosterone (CORT) to investigate the direct effects. In addition, MCF7 cells were cultured in conditioned media (CM) from primary adipose tissue excised from CORT-supplemented lean and obese male rats.. CORT alone resulted in dose-dependent increases in p27 and hypophosphorylated retinoblastoma protein (Rb) which was accompanied by a reduction in the number of cells in S-phase. CM prepared from adipose tissue overrode these direct CORT effects, suggesting that the tumor growth microenvironment created in the CM dominates MCF7 cell cycle regulation.. The direct inhibitory effects of CORT on cancer cell cycle progression are largely limited by the hormone's effects on adipose tissue biology.

    Topics: Adiponectin; Adipose Tissue; Animals; Breast Neoplasms; Cell Cycle; Cell Proliferation; Corticosterone; Epididymis; Female; Humans; Leptin; Male; MCF-7 Cells; Obesity; Proliferating Cell Nuclear Antigen; Rats, Sprague-Dawley; Retinoblastoma Protein; RNA, Messenger; Tumor Microenvironment

2015
Effects of Obesity and Obesity-Related Molecules on Canine Mammary Gland Tumors.
    Veterinary pathology, 2015, Volume: 52, Issue:6

    Obesity can affect the clinical course of a number of diseases, including breast cancer in women and mammary gland tumors in female dogs, via the secretion of various cytokines and hormones. The objective of this study was to examine the expression patterns of obesity-related molecules such as aromatase, leptin, and insulin-like growth factor 1 receptor (IGF-1 R) in canine mammary carcinomas (CMCs) on the basis of the body condition score (BCS). Comparative analyses of the expression of these molecules, together with prognostic factors for CMCs, including hormone receptors (HRs; estrogen and progesterone receptors), lymphatic invasion, central necrosis of the tumor, and histologic grade, were performed on 56 CMCs. The mean age of CMC onset was lower in the overweight or obese group (8.7 ± 1.9 years) than in the lean or ideal body weight group (10.4 ± 2.7 years). The proportion of poorly differentiated (grade III) tumors was significantly higher in the overweight or obese female dogs. Aromatase expression was significantly higher in the overweight or obese group and was correlated with the expression of HRs (P = .025). These findings suggest that overweight or obese status might affect the development and behavior of CMCs by tumor-adipocyte interactions and increased HR-related tumor growth.

    Topics: Animals; Aromatase; Breast Neoplasms; Dogs; Female; Leptin; Mammary Glands, Animal; Mammary Neoplasms, Animal; Obesity; Receptor, IGF Type 1; Receptors, Estrogen; Receptors, Progesterone

2015
Chronic-leptin attenuates Cisplatin cytotoxicity in MCF-7 breast cancer cell line.
    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2015, Volume: 36, Issue:1

    Large-scale epidemiological studies support a correlation between obesity and breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play a significant role in mammary tumor formation and progression. Moreover, regulation of oxidative stress is another important factor in both tumor development and responses to anticancer therapies. The aim of this study was to examine the relationship between oxidative stress and chronic leptin exposure.. We treated MCF-7 breast cancer cells with 100 ng/mL leptin for 10 days and analyzed cell growth, ROS production and oxidative damage, as well as, some of the main antioxidant systems. Furthermore, since the hyperleptinemia has been associated with a worse pathology prognosis, we decided to test the influence of leptin in response to cisplatin anticancer treatment.. Leptin signalling increased cell proliferation but reduced ROS production, as well as, oxidative damage. We observed an upregulation of SIRT1 after leptin exposure, a key regulator of stress response and metabolism. Additionally, leptin counteracted cisplatin-induced cytotoxicity in tumor cells, showing a decrease in cell death.. Chronic leptin could contribute to the effective regulation of endogenous and treatment-induced oxidative stress, and it contributes to explain in part its proliferative effects.

    Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Survival; Cisplatin; Female; Humans; Leptin; MCF-7 Cells; Oxidative Stress; Reactive Oxygen Species; Sirtuin 1; Up-Regulation

2015
Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-β-catenin signaling axis in a microRNA-34a dependent manner.
    Oncotarget, 2015, Jun-30, Volume: 6, Issue:18

    Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor-xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling-network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-β-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK-mediated inhibition of Wnt1-MTA1-β-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1-β-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-β-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-β-catenin axis.

    Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Biphenyl Compounds; Breast Neoplasms; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin D1; Drugs, Chinese Herbal; Female; Histone Deacetylases; Humans; Leptin; Lignans; Magnolia; MCF-7 Cells; Mice; Mice, Nude; Mice, Obese; MicroRNAs; Neoplasm Invasiveness; Obesity; Phosphorylation; Plant Extracts; Promoter Regions, Genetic; Repressor Proteins; RNA Interference; RNA, Small Interfering; Signal Transduction; Spheroids, Cellular; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Wnt1 Protein; Xenograft Model Antitumor Assays

2015
Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells.
    Cancer biology & therapy, 2015, Volume: 16, Issue:8

    Previous studies have revealed that leptin may be involved in epithelial-mesenchymal transition (EMT), a crucial initiator of cancer progression to facilitate metastatic cascade, increase tumor recurrence, and ultimately cause poor prognosis. However, the underlying mechanism remains unclear. The aim of our present study was to investigate the effect of leptin on EMT of breast cancer cells and the underlying mechanism.. Our data demonstrated that leptin significantly increased the phosphorylation of STAT3, Akt, and ERK1/2, elevated the expression of IL-8, and induced breast cancer cells to undergo EMT. The effect of leptin on IL-8 could visibly abolished by the inhibitor of PI3K LY294002. In addition, leptin-induced EMT of breast cancer cells was blocked by anti-IL-8 antibodies. Examination of the expression of ObR, leptin, IL-8 and EMT-related biomarkers in patient specimens demonstrated that malignant breast carcinoma with lymph node metastases (LNM), which represents poor prognosis, expressed higher levels of ObR, leptin, IL-8 than other types of breast cancer, and displayed more obvious EMT transversion. In vivo xenograft experiment revealed that leptin signally promoted tumor growth and metastasis and increased the expressions of IL-8 and EMT-related biomarkers.. Our results support that leptin-induced EMT in breast cancer cells requires IL-8 activation via the PI3K/Akt signal pathway.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Female; Humans; Interleukin-8; Leptin; MCF-7 Cells; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor

2015
Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors.
    Nutrients, 2015, Jun-26, Volume: 7, Issue:7

    Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage. While intentional weight loss is thought to improve prognosis, its impact on these adipokines is unclear. This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during weight loss. Given the controversies about what dietary pattern is most appropriate for breast cancer control and regulation of adipokine metabolism, the effect of a low fat versus a low carbohydrate pattern was evaluated using a non-randomized, controlled study design. Anthropometric data and fasted plasma were obtained monthly during the six-month weight loss intervention. While leptin was associated with fat mass, adiponectin was not, and the lack of correlation between leptin and adiponectin concentrations throughout weight loss implies independent mechanisms of regulation. The temporal pattern of change in leptin but not adiponectin was affected by magnitude of weight loss. Dietary pattern was without effect on either adipokine. Mechanisms not directly related to dietary pattern, weight loss, or fat mass appear to play dominant roles in the regulation of circulating levels of these adipokines.

    Topics: Adiponectin; Anthropometry; Biomarkers; Body Mass Index; Breast Neoplasms; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Female; Humans; Leptin; Middle Aged; Overweight; Postmenopause; Prognosis; Survivors; Time Factors; Weight Loss

2015
Circulating Adipokines and Inflammatory Markers and Postmenopausal Breast Cancer Risk.
    Journal of the National Cancer Institute, 2015, Volume: 107, Issue:9

    Adipokines and inflammation may provide a mechanistic link between obesity and postmenopausal breast cancer, yet epidemiologic data on their associations with breast cancer risk are limited.. In a case-cohort analysis nested within the Women's Health Initiative Observational Study, a prospective cohort of postmenopausal women, baseline plasma samples from 875 incident breast cancer case patients and 839 subcohort participants were tested for levels of seven adipokines, namely leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α, hepatocyte growth factor, and plasminogen activator inhibitor-1, and for C-reactive protein (CRP), an inflammatory marker. Data were analyzed by multivariable Cox modeling that included established breast cancer risk factors and previously measured estradiol and insulin levels. All statistical tests were two-sided.. The association between plasma CRP levels and breast cancer risk was dependent on hormone therapy (HT) use at baseline (P interaction = .003). In a model that controlled for multiple breast cancer risk factors including body mass index (BMI), estradiol, and insulin, CRP level was positively associated with breast cancer risk among HT nonusers (hazard ratio for high vs low CRP levels = 1.67, 95% confidence interval = 1.04 to 2.68, P trend = .029). None of the other adipokines were statistically significantly associated with breast cancer risk. Following inclusion of CRP, insulin, and estradiol in a multivariable model, the association of BMI with breast cancer was attenuated by 115%.. These data indicate that CRP is a risk factor for postmenopausal breast cancer among HT nonusers. Inflammatory mediators, together with insulin and estrogen, may play a role in the obesity-breast cancer relation.

    Topics: Adipokines; Adiponectin; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Estradiol; Female; Hepatocyte Growth Factor; Humans; Inflammation; Insulin; Interleukin-6; Leptin; Middle Aged; Obesity; Odds Ratio; Plasminogen Activator Inhibitor 1; Postmenopause; Proportional Hazards Models; Prospective Studies; Resistin; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha

2015
Differential crosstalk between the AMPK and PI3K/Akt pathways in breast cancer cells of differing genotypes: Leptin inhibits the effectiveness of AMPK activation.
    Oncology reports, 2015, Volume: 34, Issue:4

    AMP-activated protein kinase (AMPK), a sensor of cellular energy, is widely reported as a potential therapeutic target in treatment of breast and other cancers. The activated enzyme has been shown to be a promising anti-proliferative agent in breast cancer cell lines. However, little data exist on crosstalk between AMPK and the cellular survival axis of PI3K/Akt/mTOR pathway and the impact of microenvironment on cellular responses to AMPK activation. We present results which show differential crosstalk between AMPK and Akt, dependent on the cellular genetics of each breast cancer cell type. We also show that leptin blocks activation of AMPK and partially or completely attenuates the anti-proliferative effect of AMPK activation depending on the cell type. This suggests that leptin within the local environment might impose limitations on therapeutic usage of AMPK activators in cancer, thereby attenuating their effective use in many obese subjects.

    Topics: AMP-Activated Protein Kinases; Breast Neoplasms; Cell Line, Tumor; Enzyme Activation; Female; Gene Expression Regulation, Neoplastic; Genotype; Humans; Leptin; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Microenvironment

2015
Leptin produced by obese adipose stromal/stem cells enhances proliferation and metastasis of estrogen receptor positive breast cancers.
    Breast cancer research : BCR, 2015, Aug-19, Volume: 17

    The steady increase in the incidence of obesity among adults has been paralleled with higher levels of obesity-associated breast cancer. While recent studies have suggested that adipose stromal/stem cells (ASCs) isolated from obese women enhance tumorigenicity, the mechanism(s) by which this occurs remains undefined. Evidence suggests that increased adiposity results in increased leptin secretion from adipose tissue, which has been shown to increased cancer cell proliferation. Previously, our group demonstrated that ASCs isolated from obese women (obASCs) also express higher levels of leptin relative to ASCs isolated from lean women (lnASCs) and that this obASC-derived leptin may account for enhanced breast cancer cell growth. The current study investigates the impact of inhibiting leptin expression in lnASCs and obASCs on breast cancer cell (BCC) growth and progression.. Estrogen receptor positive (ER+) BCCs were co-cultured with leptin shRNA lnASCs or leptin shRNA obASCs and changes in the proliferation, migration, invasion, and gene expression of BCCs were investigated. To assess the direct impact of leptin inhibition in obASCs on BCC proliferation, MCF7 cells were injected alone or mixed with control shRNA obASCs or leptin shRNA obASCs into SCID/beige mice.. ER+ BCCs were responsive to obASCs during direct co-culture, whereas lnASCs were unable to increase ER(+) BCC growth. shRNA silencing of leptin in obASCs negated the enhanced proliferative effects of obASC on BCCs following direct co-culture. BCCs co-cultured with obASCs demonstrated enhanced expression of epithelial-to-mesenchymal transition (EMT) and metastasis genes (SERPINE1, MMP-2, and IL-6), while BCCs co-cultured with leptin shRNA obASCs did not display similar levels of gene induction. Knockdown of leptin significantly reduced tumor volume and decreased the number of metastatic lesions to the lung and liver. These results correlated with reduced expression of both SERPINE1 and MMP-2 in tumors formed with MCF7 cells mixed with leptin shRNA obASCs, when compared to tumors formed with MCF7 cells mixed with control shRNA obASCs.. This study provides mechanistic insight as to how obesity enhances the proliferation and metastasis of breast cancer cells; specifically, obASC-derived leptin contributes to the aggressiveness of breast cancer in obese women.

    Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Breast; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Coculture Techniques; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Leptin; Matrix Metalloproteinase 2; MCF-7 Cells; Mice; Mice, SCID; Neoplasm Metastasis; Obesity; Plasminogen Activator Inhibitor 1; Receptors, Estrogen; RNA, Small Interfering; Stem Cells; Stromal Cells

2015
Honokiol activates LKB1-miR-34a axis and antagonizes the oncogenic actions of leptin in breast cancer.
    Oncotarget, 2015, Oct-06, Volume: 6, Issue:30

    Leptin, a major adipocytokine produced by adipocytes, is emerging as a key molecule linking obesity with breast cancer therefore, it is important to find effective strategies to antagonize oncogenic effects of leptin to disrupt obesity-cancer axis. Here, we examine the potential of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, as a leptin-antagonist and systematically elucidate the underlying mechanisms. HNK inhibits leptin-induced epithelial-mesenchymal-transition (EMT), and mammosphere-formation along with a reduction in the expression of stemness factors, Oct4 and Nanog. Investigating the downstream mediator(s), that direct leptin-antagonist actions of HNK; we discovered functional interactions between HNK, LKB1 and miR-34a. HNK increases the expression and cytoplasmic-localization of LKB1 while HNK-induced SIRT1/3 accentuates the cytoplasmic-localization of LKB1. We found that HNK increases miR-34a in LKB1-dependent manner as LKB1-silencing impedes HNK-induced miR-34a which can be rescued by LKB1-overexpression. Finally, an integral role of miR-34a is discovered as miR-34a mimic potentiates HNK-mediated inhibition of EMT, Zeb1 expression and nuclear-localization, mammosphere-formation, and expression of stemness factors. Leptin-antagonist actions of HNK are further enhanced by miR-34a mimic whereas miR-34a inhibitor results in inhibiting HNK's effect on leptin. These data provide evidence for the leptin-antagonist potential of HNK and reveal the involvement of LKB1 and miR-34a.

    Topics: AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Blotting, Western; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Leptin; Lignans; MCF-7 Cells; Mice; MicroRNAs; Microscopy, Confocal; Protein Serine-Threonine Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Xenograft Model Antitumor Assays

2015
Evaluation of CYP17A1 and LEP Gene Polymorphisms in Breast Cancer.
    Oncology research and treatment, 2015, Volume: 38, Issue:9

    Polymorphisms of estrogen synthesis- and adiposity-related genes can contribute to the development of breast cancer. The purpose of the current study was to analyze the association between CYP17A1 T27C (rs743572) and LEP -2548G>A (rs7799039) gene polymorphisms and breast cancer.. 199 breast cancer patients and 197 healthy controls were included in the study. The CYP17A1 and LEP gene polymorphisms were determined using polymerase chain reaction-based restriction fragment length polymorphism analysis.. No statistically significant association was found between these polymorphisms and breast cancer risk among a Turkish population. However, stratified analysis of these polymorphisms in relation to different clinicopathological characteristics of breast cancer revealed an association between breast cancer diagnosis and the CYP17A1 T27C polymorphism (p = 0.024).. Our study suggests no strong association between the CYP17A1 T27C and LEP -2548G>A polymorphisms and the incidence of breast cancer in Turkish women. The potential association between CYP17A1 T27C and the type of breast cancer deserves further consideration.

    Topics: Biomarkers, Tumor; Breast Neoplasms; Female; Genetic Association Studies; Genetic Markers; Genetic Predisposition to Disease; Humans; Leptin; Middle Aged; Polymorphism, Single Nucleotide; Prevalence; Reproducibility of Results; Risk Factors; Sensitivity and Specificity; Steroid 17-alpha-Hydroxylase

2015
Relationship of obesity with serum concentrations of leptin, CRP and IL-6 in breast cancer survivors.
    Journal of the Egyptian National Cancer Institute, 2015, Volume: 27, Issue:4

    Several mechanisms have been proposed to explain the adverse effect of obesity on quality of life among women with breast cancer, including alteration in some inflammatory markers. The aim of this study was to determine the status of serum levels of leptin, IL-6 and CRP in obese, overweight and normal weight breast cancer survivors in order to determine the relationship between inflammatory markers' levels and obesity.. This cross-sectional study was done on 75 women with breast cancer, 30 obese, 15 overweight and 30 normal weight patients. Serum leptin, IL-6, CRP, total protein, albumin and lipid profile as well as anthropometric parameters were measured in three groups.. Serum leptin levels of obese patients were significantly higher than those of overweight and normal weight patients (P<0.05). Higher serum CRP and lower albumin levels were observed in obese patients in comparison with normal weight patients (P<0.05). HDL-C level was significantly different between overweight and normal weight patients (P<0.05). Significant differences in serum IL-6 levels were not observed between the study groups (P>0.05). Moreover, multiple regression analysis showed that leptin was significantly associated with BMI (P<0.001), while albumin was negatively correlated with BMI (P<0.05). CRP levels were significantly correlated with BMI and waist-to-hip ratio (WHR) (P<0.05).. In conclusion, high leptin levels and alteration in acute phase proteins in obese patients may exaggerate the inflammation status. As inflammation has the potential to increase the susceptibility of the patients to metastasis development, it is necessary to decline its rate.

    Topics: Adult; Biomarkers; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Inflammation Mediators; Interleukin-6; Leptin; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Obesity; Risk Factors; Survivors

2015
Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells.
    Cancer prevention research (Philadelphia, Pa.), 2015, Volume: 8, Issue:12

    Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of breast cancer.

    Topics: Adiponectin; Adolescent; Adult; Breast; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Epithelial Cells; Female; Humans; Leptin; Microscopy, Confocal; Middle Aged; Obesity; Stem Cells; Young Adult

2015
Serum irisin levels are lower in patients with breast cancer: association with disease diagnosis and tumor characteristics.
    BMC cancer, 2015, Nov-11, Volume: 15

    Irisin is a recently discovered myokine, involved in the browning of white adipose tissue. To date, its function has been mainly associated with energy homeostasis and metabolism, and it has been proposed as a promising therapeutic target for obesity and metabolic diseases. This is the first study investigating the role of irisin in human breast cancer.. Participants included one hundred and one (101) female patients with invasive ductal breast cancer and fifty one (51) healthy women. Serum levels of irisin, leptin, adiponectin and resistin were quantified in duplicates by ELISA. Serum levels of CEA, CA 15-3 and Her-2/neu were measured on an immunology analyzer. The association between irisin and breast cancer was examined by logistic regression analysis. The feasibility of serum irisin in discriminating breast cancer patients was assessed by ROC curve analysis. Potential correlations with demographic, anthropometric and clinical parameters, with markers of adiposity and with breast tumor characteristics were also investigated.. Serum levels of irisin were significantly lower in breast cancer patients compared to controls (2.47 ± 0.57 and 3.24 ± 0.66 μg/ml, respectively, p < 0.001). A significant independent association between irisin and breast cancer was observed by univariate and multivariate analysis (p < 0.001). It was estimated that a 1 unit increase in irisin levels leads to a reduction in the probability of breast cancer by almost 90%. Irisin could effectively discriminate breast cancer patients at a cut-off point of 3.21 μg/ml, with 62.7% sensitivity and 91.1% specificity. A positive association with tumor stage and marginal associations with tumor size and lymph node metastasis were observed (p < 0.05, p < 0.01, p < 0.01, respectively).. Our novel findings implicate irisin in breast cancer and suggest its potential application as a new diagnostic indicator of the presence of disease.

    Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Carcinoma, Ductal, Breast; Case-Control Studies; Female; Fibronectins; Humans; Leptin; Logistic Models; Middle Aged; Sensitivity and Specificity

2015
Breast Cancer Cell Colonization of the Human Bone Marrow Adipose Tissue Niche.
    Neoplasia (New York, N.Y.), 2015, Volume: 17, Issue:12

    Bone is a preferred site of breast cancer metastasis, suggesting the presence of tissue-specific features that attract and promote the outgrowth of breast cancer cells. We sought to identify parameters of human bone tissue associated with breast cancer cell osteotropism and colonization in the metastatic niche.. Migration and colonization patterns of MDA-MB-231-fLuc-EGFP (luciferase-enhanced green fluorescence protein) and MCF-7-fLuc-EGFP breast cancer cells were studied in co-culture with cancellous bone tissue fragments isolated from 14 hip arthroplasties. Breast cancer cell migration into tissues and toward tissue-conditioned medium was measured in Transwell migration chambers using bioluminescence imaging and analyzed as a function of secreted factors measured by multiplex immunoassay. Patterns of breast cancer cell colonization were evaluated with fluorescence microscopy and immunohistochemistry.. Enhanced MDA-MB-231-fLuc-EGFP breast cancer cell migration to bone-conditioned versus control medium was observed in 12/14 specimens (P = .0014) and correlated significantly with increasing levels of the adipokines/cytokines leptin (P = .006) and IL-1β (P = .001) in univariate and multivariate regression analyses. Fluorescence microscopy and immunohistochemistry of fragments underscored the extreme adiposity of adult human bone tissues and revealed extensive breast cancer cell colonization within the marrow adipose tissue compartment.. Our results show that breast cancer cells migrate to human bone tissue-conditioned medium in association with increasing levels of leptin and IL-1β, and colonize the bone marrow adipose tissue compartment of cultured fragments. Bone marrow adipose tissue and its molecular signals may be important but understudied components of the breast cancer metastatic niche.

    Topics: Adipocytes; Adipose Tissue; Bone and Bones; Bone Marrow; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular Microenvironment; Coculture Techniques; Culture Media, Conditioned; Female; Green Fluorescent Proteins; Humans; Immunohistochemistry; Interleukin-1beta; Leptin; Logistic Models; Luciferases; Male; MCF-7 Cells; Microscopy, Confocal; Microscopy, Fluorescence; Multivariate Analysis

2015
Obesity induced a leptin-Notch signaling axis in breast cancer.
    International journal of cancer, 2014, Apr-01, Volume: 134, Issue:7

    To investigate whether obesity induces a leptin-Notch signaling axis in breast cancer (BC), leptin-induced Notch was determined in human MCF-7 and MDA-MB231 and mouse E0771 cells and in E0771-BC hosted by syngeneic lean and diet-induced obesity (DIO) C57BL/6J female mice. Lean and DIO mice were treated for 3 weeks with leptin inhibitor (PEG-LPrA2) 1 week after the inoculation of E0771 cells. Leptin induced Notch1, 3 and 4 in BC cells, but Notch2 expression showed opposite pattern in MCF-7 compared to MDA-MB231 cells. Notch loss-of-function (DAPT and dominant negative [R218H] RBP-Jk [CSL/CBF1]) showed that a functional leptin-Notch signaling axis was involved in the proliferation and migration of E0771 cells. E0771-BC onset was affected by obesity (lean mice7/10 [70%] vs. DIO mice: 11/12 [92%]; Pearson χ(2) : p = 0.06]). PEG-LPrA2 significantly reduced BC growth (untreated: 19/42; [45%] vs. treated: 8/42 [19%]; Pearson χ(2) : p = 0.008). PEG-LPrA2 did not influence the caloric intake of mice but increased carcass and/or body weights of lean and DIO mice inoculated with E0771 cells, which could be related to the improvement of health conditions (less aggressive disease). Importantly, BC from obese mice had higher levels of Notch3, JAG1 and survivin than lean mice. Inhibition of leptin signaling reduced protein levels of Notch (NICD1, NICD4, Notch3, JAG1 and survivin) and significantly decreased mRNA expression of Notch receptors, ligands and targets. PEG-LPrA's effects were more prominent in DIO mice. Present data suggest that leptin induces Notch, which could be involved in the reported higher incidence and aggressiveness and, poor prognosis of BC in obese patients.

    Topics: Animals; Body Weight; Breast Neoplasms; Calcium-Binding Proteins; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Female; Humans; Inhibitor of Apoptosis Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Leptin; MCF-7 Cells; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Receptors, Notch; Repressor Proteins; Serrate-Jagged Proteins; Signal Transduction; Survivin

2014
Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway.
    Molecular medicine reports, 2014, Volume: 9, Issue:1

    Obesity has been associated with an increased risk of postmenopausal breast cancer, which may be due to the expression of leptin. The aim of this study was to determine the role of leptin in the growth of breast cancer cells in nude mice, the proliferation and migration of MCF-7 human breast cancer cells and its downstream signaling pathway. The xenograft mouse model was elicited by injecting MCF-7 human breast cancer cells into the left back axilla and the tumor size was measured every other day. Leptin injected subcutaneously around the tumor site led to an increase in the size and weight of the tumor, whereas the leptin antagonist (LA) significantly inhibited the size and weight of the tumor. Leptin promoted the proliferation and migration of MCF-7 cells and LA inhibited it. The effects of leptin on increasing the size and weight of the tumor in the nude mice and the proliferation and migration of MCF-7 human breast cancer cells were eradicated by pretreatment with LA, the extracellular-signal regulated kinase (ERK) inhibitor PD98059. In the xenograft mouse model the leptin level was increased and leptin increased the phosphorylation of ERK in the MCF-7 cells, whereas LA significantly reduced the phosphorylation of ERK. These results indicated that leptin promotes the growth of breast cancer in the nude mice and increases the proliferation and migration of MCF-7 human breast cancer cells via the ERK pathway.

    Topics: Animals; Breast Neoplasms; Cell Movement; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Flavonoids; Humans; Leptin; MCF-7 Cells; Mice; Mice, Nude; Phosphorylation; Transplantation, Heterologous

2014
Inhibition of leptin and leptin receptor gene expression by silibinin-curcumin combination.
    Asian Pacific journal of cancer prevention : APJCP, 2014, Volume: 14, Issue:11

    Leptin and its receptor are involved in breast carcinogenesis as mitogenic factors. Therefore, they could be considered as targets for breast cancer therapy. Expression of the leptin receptor gene could be modulated by leptin secretion. Silibinin and curcumin are herbal compounds with anti-cancer activity against breast cancer. The aim of this study was to assess their potential to inhibit of expression of the leptin gene and its receptor and leptin secretion. Cytotoxic effects of the two agents on combination on T47D breast cancer cells was investigated by MTT assay test after 24h treatment. With different concentrations the levels of leptin, leptin receptor genes expression were measured by reverse-transcription real-time PCR. Amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. The silibinin and curcumin combination inhibited growth of T47D cells in a dose dependent manner. There were also significant difference between control and treated cells in leptin expression and the quantity of secreted leptin with a relative decrease in leptin receptor expression. In conclusion, these herbal compounds inhibit the expression and secretion of leptin and it could probably be used as drug candidates for breast cancer therapy through leptin targeting in the future.

    Topics: Antineoplastic Agents; Antioxidants; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Signal Transduction; Silybin; Silymarin

2014
Effects of tomato and soy on serum adipokine concentrations in postmenopausal women at increased breast cancer risk: a cross-over dietary intervention trial.
    The Journal of clinical endocrinology and metabolism, 2014, Volume: 99, Issue:2

    Breast cancer risk among postmenopausal women increases as body mass index increases. Practical preventive methods to reduce risk of breast cancer are lacking. Few studies have investigated the effects of carotenoids and isoflavones on circulating adipokines in postmenopausal women.. The aim was to examine the effects of lycopene- and isoflavone-rich diets on serum adipokines.. This was a 26-week, two-arm, longitudinal crossover trial.. Participants were recruited from clinics at The Ohio State University Comprehensive Cancer Center.. Seventy postmenopausal women at increased breast cancer risk participated in the study. The mean age and body mass index of participants was 57.2 years and 30.0 kg/m(2), respectively; the study was comprised of 81.4% whites.. The interventions included 10 weeks of consumption of a tomato-based diet (≥25 mg lycopene daily) and 10 weeks of consumption of a soy-based diet (≥40 g of soy protein daily), with a 2-week washout in between.. Changes in serum adiponectin, leptin, and the adiponectin to leptin ratio were examined for each intervention through linear mixed models, with ratio estimates corresponding to postintervention adipokine concentrations relative to preintervention concentrations.. After the tomato intervention, among all women, adiponectin concentration increased (ratio 1.09, 95% confidence interval (CI) 1.00-1.18), with a stronger effect observed among nonobese women (ratio 1.13, 95% CI 1.02-1.25). After the soy intervention, adiponectin decreased overall (ratio 0.91, 95% CI 0.84-0.97), with a larger reduction observed among nonobese women (ratio 0.89, 95% CI 0.81-0.98). Overall, no significant changes in leptin or the adiponectin to leptin ratio were observed after either intervention.. Increasing dietary consumption of tomato-based foods may beneficially increase serum adiponectin concentrations among postmenopausal women at increased breast cancer risk, especially those who are not obese. Additional studies are essential to confirm these effects and to elucidate the specific mechanisms that may make phytonutrients found in tomatoes practical as breast cancer chemopreventive agents.

    Topics: Adiponectin; Adult; Aged; Body Mass Index; Breast Neoplasms; Cross-Over Studies; Diet; Female; Humans; Leptin; Middle Aged; Postmenopause; Risk; Solanum lycopersicum; Soybean Proteins

2014
Leptin induces CYP1B1 expression in MCF-7 cells through ligand-independent activation of the ERα pathway.
    Toxicology and applied pharmacology, 2014, May-15, Volume: 277, Issue:1

    Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor α (ERα), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERα knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ERα-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ERα at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ERα activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ERα phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ERα pathway as a result of the activation of ERK and Akt in MCF-7 cells.

    Topics: Aryl Hydrocarbon Hydroxylases; Breast Neoplasms; Cell Line, Tumor; Cytochrome P-450 CYP1B1; Estrogen Receptor alpha; Estrogens, Catechol; Female; Humans; Leptin; MCF-7 Cells; Phosphorylation; Response Elements; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transcriptional Activation; Transfection; Up-Regulation

2014
Leptin induces a proliferative response in breast cancer cells but not in normal breast cells.
    Nutrition and cancer, 2014, Volume: 66, Issue:4

    Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, a hormone excessively produced during obesity, is suggested to be involved in breast cancer. The aim of the study was to investigate procarcinogenic potential of leptin by evaluating influence of leptin on cell proliferation, cell cycle, apoptosis, and signaling on numerous breast cells lines, including 184B5 normal cells, MCF10A fibrocystic cells and MCF-7, MDA-MB-231, and T47D cancer cells. Expressions of leptin and Ob-R were analyzed using qRT-PCR and immunohistochemistry, proliferation using fluorimetric resazurin reduction test and xCELLigence system, apoptosis and cell cycle by flow cytometry, and effect of leptin on different signalling pathways using qRT-PCR and Western blot. Cells were exposed to increasing concentrations of leptin. All cell lines expressed mRNA and protein of leptin and Ob-R. Leptin stimulated proliferation of all cell lines except for 184B5 and MDA-MB-231 cells. Leptin inhibited apoptosis but didn't alter proportion of cells within cell cycle in MCF7 cells. Leptin induced overexpression of leptin, Ob-R, estrogen receptor, and aromatase mRNA in MCF-7 and T47D cells. Autoregulation induced by leptin, relationship with estrogen pathway, and proliferative and antiapoptic activity in breast cancer cells may explain that obesity-associated hyperleptinemia may be a breast cancer risk factor.

    Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Proliferation; Female; Fibrocystic Breast Disease; Humans; Immunohistochemistry; Leptin; MCF-7 Cells; Obesity; Receptors, Leptin; Signal Transduction

2014
Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats.
    The Journal of nutritional biochemistry, 2014, Volume: 25, Issue:6

    The present study investigated whether early life exposure to high levels of animal fat increases breast cancer risk in adulthood in rats. Dams consumed a lard-based high-fat (HF) diet (60% fat-derived energy) or an AIN93G control diet (16% fat-derived energy) during gestation or gestation and lactation. Their 7-week-old female offspring were exposed to 7,12-dimethyl-benzo[a]anthracene to induce mammary tumors. Pregnant dams consuming an HF diet had higher circulating leptin levels than pregnant control dams. However, compared to the control offspring, significantly lower susceptibility to mammary cancer development was observed in the offspring of dams fed an HF diet during pregnancy (lower tumor incidence, multiplicity and weight), or pregnancy and lactation (lower tumor multiplicity only). Mammary epithelial elongation, cell proliferation (Ki67) and expression of NFκB p65 were significantly lower and p21 expression and global H3K9me3 levels were higher in the mammary glands of rats exposed to an HF lard diet in utero. They also tended to have lower Rank/Rankl ratios (P=.09) and serum progesterone levels (P=.07) than control offspring. In the mammary glands of offspring of dams consuming an HF diet during both pregnancy and lactation, the number of terminal end buds, epithelial elongation and the BCL-2/BAX ratio were significantly lower and serum leptin levels were higher than in the controls. Our data confirm that the breast cancer risk of offspring can be programmed by maternal dietary intake. However, contrary to our expectation, exposure to high levels of lard during early life decreased later susceptibility to breast cancer.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biomarkers; Breast Neoplasms; Diet, High-Fat; Dietary Fats; Disease Resistance; Female; Fetal Development; Gene Expression Regulation, Developmental; Kaplan-Meier Estimate; Lactation; Leptin; Mammary Glands, Animal; Maternal Nutritional Physiological Phenomena; Pregnancy; Progesterone; Rats, Sprague-Dawley; Tumor Burden

2014
Estradiol affects extracellular leptin:adiponectin ratio in human breast tissue in vivo.
    The Journal of clinical endocrinology and metabolism, 2014, Volume: 99, Issue:9

    Exposure to sex steroids is associated with increased breast cancer risk, and adipokines, leptin and adiponectin have been implicated in cancer progression. However, it is not known whether sex steroids affect adipokine secretion in breast tissue.. To elucidate the role of estrogen and tamoxifen on adipokine release in normal human breast tissue and breast cancer.. Microdialysis sampling was used to collect extracellular in vivo leptin and adiponectin from normal human breast tissue in premenopausal healthy volunteers during the menstrual cycle and in postmenopausal women before tamoxifen treatment and after 6 weeks of treatment. In women with breast cancer, microdialysis was performed intratumorally before surgery. In addition, whole normal breast tissue biopsies were cultured ex vivo, and murine breast cancer models were evaluated.. In normal breast tissue, plasma estradiol negatively correlated with local extracellular adiponectin levels (r = -0.34; P < .05) and positively correlated with leptin (r = 0.37; P < .05) and leptin:adiponectin ratio (r = 0.38; P < .05). In postmenopausal women, tamoxifen treatment increased adiponectin (P < 0.05) and decreased leptin (P < .01) and the leptin:adiponectin ratio (P < .01). These in vivo results were confirmed in breast tissue biopsies cultured ex vivo. In patients with breast cancer, extracellular leptin was higher (P < .01) and adiponectin lower (P < .05) in tumors than in normal adjacent breast tissue. In a murine model of breast cancer, estrogen exposure increased leptin secretion (P < .05).. Estrogen exposure may have a critical role in the regulation of adipokines in human breast tissue and may serve as therapeutic targets for treatment and prevention.

    Topics: Adiponectin; Adult; Aged; Animals; Antineoplastic Agents, Hormonal; Breast; Breast Neoplasms; Cells, Cultured; Disease Models, Animal; Estradiol; Estrogens; Extracellular Space; Female; Humans; Leptin; Mice; Mice, Inbred BALB C; Mice, Nude; Microdialysis; Middle Aged; Postmenopause; Premenopause; Subcutaneous Fat; Tamoxifen; Young Adult

2014
Genetic variation in adipokine genes and associations with adiponectin and leptin concentrations in plasma and breast tissue.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2014, Volume: 23, Issue:8

    Circulating adipokines may be associated with breast cancer risk. Genetic variants governing adipokines and adipokine receptors may also predict risk, but their effect on breast adipokine concentrations is unknown.. We conducted a cross-sectional analysis of functional SNPs in 5 adipokine genes [adiponectin, leptin (LEP), and their receptors] among 85 cancer-free women who were undergoing reduction mammoplasty.. In multivariable-adjusted regression models, compared with the common GG genotype, the AA genotype of the LEP A19G SNP was associated with 27% lower plasma adiponectin [ratio, 0.73; 95% confidence interval (CI), 0.54-0.98] and leptin (ratio, 0.73; 95% CI, 0.55-0.96). Women with the AG genotype of LEP A19G had 39% lower breast leptin (ratio, 0.61; 95% CI, 0.39-0.97) compared with those with the GG genotype. No associations were observed for SNPs in the remaining genes.. Genetic variation in LEP may alter endogenous adipokine concentrations in circulation and in breast tissues.. These preliminary findings may support the hypothesis that genetic variation in adipokine genes modifies circulating adipokine concentrations and possibly leptin concentrations in local breast tissues, which may be associated with breast cancer risk.

    Topics: Adipokines; Adiponectin; Adult; Breast Neoplasms; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Receptors, Adiponectin; Receptors, Leptin

2014
Increased TNF α, IL-6 and ErbB2 mRNA expression in peripheral blood leukocytes from breast cancer patients.
    Medical oncology (Northwood, London, England), 2014, Volume: 31, Issue:8

    Obesity has been associated with increased incidence and mortality of breast cancer. The precise relation between obesity and breast cancer is yet to be determined, with few studies linking them with altered serum levels adipokines and inflammatory cytokines. The relevance of the expression of genes encoding for adipokines and inflammatory cytokines in the peripheral blood and their contribution to obesity and breast cancer has not been fully investigated. We aim to identify potential transcriptional biomarkers in blood samples that may assist to underpin the link between obesity and breast cancer. Therefore, have investigated whether or not the expression levels, of selected genes [tumor necrosis factor-α (TNFα), interleukin 6 (IL-6), adiponectin, leptin, C-reactive protein (CRP), parathyroid hormone (PTH), tumor protein 53 (TP53) and erythroblastic leukemia viral oncogene 2 (ErbB2)] were altered in blood samples of lean, overweight/obese and breast cancer subjects. Blood samples were obtained from 37 lean, 19 overweight/obese and 12 breast cancer patients. Real-time polymerase chain reaction assays were performed to detect TNFα, IL-6, adiponectin, leptin, CRP, PTH, TP53 and ErbB2 gene transcripts. Transcript levels of TNFα were significantly higher by 1.4-fold and 2.1-fold in blood cells of overweight/obese and breast cancer patients, respectively, compared with lean control subjects. Transcript levels of IL-6 were significantly higher by 2.3-fold in blood cells from breast cancer patients compared with lean control subjects with normal body mass index, and no significant difference was found in the expression level of IL-6 transcripts between overweight/obese and lean control subjects. The ErbB2 transcript levels were significantly higher by 4.72-fold compared to lean control subjects and were also significantly higher compared to overweight/obese subjects. Breast cancer and obesity are associated with altered mRNA levels of cytokines and tumor marker in peripheral blood.

    Topics: Adiponectin; Adolescent; Adult; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Leptin; Leukocytes; Middle Aged; Obesity; Overweight; Parathyroid Hormone; Receptor, ErbB-2; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53; Young Adult

2014
Serum adiponectin but not leptin at diagnosis as a predictor of breast cancer survival.
    Asian Pacific journal of cancer prevention : APJCP, 2014, Volume: 15, Issue:15

    Limited numbers of epidemiological studies have examined the relationship between adipokines and breast cancer survival. Preoperative serum levels of obesity-related adipokines (leptin and adiponectin) were here measured in 370 breast cancer patients, recruited from two hospitals in Korea. We examined the association between those adipokines and disease-free survival (DFS). The TNM stage, ER status and histological grade were aslo assessed in relation to breast cancer survival. Elevated adiponectin levels were associated with reduced DFS of breast cancer (Ptrend=0.03) among patients with normal body weight, predominantly in postmenopausal women. There was no association of leptin with breast cancer survival. In conclusion, our study suggests that high levels of adiponectin at diagnosis are associated with breast cancer survival among women with normal body weight.

    Topics: Adiponectin; Adult; Biomarkers, Tumor; Breast Neoplasms; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity; Postmenopause; Prognosis; Retrospective Studies; Risk Factors; Survival Rate

2014
Vitamin D suppresses leptin stimulation of cancer growth through microRNA.
    Cancer research, 2014, Nov-01, Volume: 74, Issue:21

    Obesity is a pandemic and major risk factor for cancers. The reduction of obesity would have been an effective strategy for cancer prevention, but the reality is that worldwide obesity has kept increasing for decades, remaining a major avoidable cancer risk secondary only to smoke. The present studies suggest that vitamin D may be an effective agent to reduce obesity-associated cancer risks in women. Molecular analyses showed that leptin increased human telomerase reverse transcriptase (hTERT) mRNA expression and cell growth through estrogen receptor-α (ERα) activation in ovarian cancer cells, which was suppressed by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The suppression was compromised when miR-498 induction by the hormone was depleted with microRNA (miRNA) sponges. In mice, high-fat diet (HFD) stimulation of ovarian tumor growth was remarkably suppressed by 1,25(OH)2D3 analogue EB1089, which was also compromised by miR-498 sponges. EB1089 did not alter HFD-induced increase in serum leptin levels but increased miR-498 and decreased the diet-induced hTERT expression in tumors. Quantitative RT-PCR analyses revealed an inverse correlation between hTERT mRNA and miR-498 in response to 1,25(OH)2D3 in estrogen-sensitive ovarian, endometrial, and breast cancers. The studies suggest that miR-498-mediated hTERT downregulation is a key event mediating the anti-leptin activity of 1,25(OH)2D3 in estrogen-sensitive tumors in women.

    Topics: Animals; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mice; MicroRNAs; Ovarian Neoplasms; Telomerase; Vitamin D

2014
Role of inflammation and oxidative stress in post-menopausal oestrogen-dependent breast cancer.
    Journal of cellular and molecular medicine, 2014, Volume: 18, Issue:12

    Weight gain and obesity are among the most important risk factors for post-menopausal oestrogen-dependent breast cancer (EDBC). Weight gain is associated with oxidative stress, which in turn promotes breast cancer progression. We carried out a prospective study in 216 consecutive post-menopausal breast cancer patients aiming to examine the correlations between traditional prognostic factors (tumour size, T, nodal, N, grading, G, and metastasis status, M), and body mass index (BMI), leptin, pro-inflammatory cytokines (Interleukin, IL,-6 and tumour necrosis factor-alpha, TNF-α), and oxidative stress (reactive oxygen species, ROS, glutathione peroxidase, GPx, superoxide dismutase, SOD) among patients with oestrogen receptor (ER)+ and ER- breast cancers. Distribution of T, N and M categories did not differ between ER+ and ER- breast cancer patients. ER- patients showed a higher incidence of G3 tumours. Weight, BMI, leptin, IL-6 and ROS were higher in ER+ compared with ER- patients. Among ER+ patients, BMI, leptin, IL-6 and ROS correlated with T and M. Leptin, IL-6 and ROS were positively correlated also with N. Among ER- patients, BMI and leptin did not correlate with any of prognostic parameters, whereas a positive correlation between IL-6, ROS and M was found. Multivariate regression analysis showed that BMI, leptin, IL-6 and ROS were predictive for T, N and M in ER+ patients. Weight gain, inflammation and oxidative stress are involved in EDBC prognosis. Their modulation through antidiabetic, anti-inflammatory and antioxidants drugs combined with endocrine therapy may constitute a targeted approach in post-menopausal EDBC.

    Topics: Aged; Body Mass Index; Breast Neoplasms; Estrogens; Female; Glutathione Peroxidase; Humans; Inflammation Mediators; Interleukin-6; Leptin; Lymphatic Metastasis; Middle Aged; Multivariate Analysis; Neoplasm Staging; Oxidative Stress; Postmenopause; Prognosis; Prospective Studies; Reactive Oxygen Species; Receptors, Estrogen; Regression Analysis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

2014
Leptin induces upregulation of sphingosine kinase 1 in oestrogen receptor-negative breast cancer via Src family kinase-mediated, janus kinase 2-independent pathway.
    Breast cancer research : BCR, 2014, Oct-25, Volume: 16, Issue:5

    Obesity is a known risk factor for breast cancer. Sphingosine kinase 1 (SK1) is an oncogenic lipid kinase that is overexpressed in breast tumours and linked with poor prognosis, however, its role in obesity-driven breast cancer was never elucidated.. Human primary and secondary breast cancer tissues were analysed for SK1 and leptin receptor expression using quantitative real-time polymerase chain reaction (qRT-PCR) assay. Leptin-induced signalling was analysed in human oestrogen receptor (ER)-positive and negative breast cancer cells using Western blotting, qRT-PCR and radiolabelling assays.. Our findings show for the first time that human primary breast tumours and associated lymph node metastases exhibit a strong correlation between SK1 and leptin receptor expression (Pearson R = 0.78 and R = 0.77, respectively, P <0.001). Both these genes are elevated in metastases of ER-negative patients and show a significant increase in patients with higher body mass index (BMI). Leptin induces SK1 expression and activation in ER-negative breast cancer cell lines MDAMB-231 and BT-549, but not in ER-positive cell lines. Pharmacological inhibition and gene knockdown showed that leptin-induced SK1 activity and expression are mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and Src family kinase (SFK) pathways, but not by the major pathways downstream of leptin receptor (LEPR) - janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Src-homology 2 domain-containing phosphatase 2 (SHP2) appeared to be key to SK1 activation, and may function as an adaptor protein between SFKs and LEPR. Importantly, leptin-induced breast cancer cell proliferation was abrogated by SK1-specific small interfering RNA (siRNA).. Overall, our findings demonstrate a novel SFK/ERK1/2-mediated pathway that links leptin signalling and expression of oncogenic enzyme SK1 in breast tumours and suggest the potential significance of this pathway in ER-negative breast cancer.

    Topics: Breast Neoplasms; Cell Proliferation; Enzyme Induction; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; Leptin; Lymphatic Metastasis; MCF-7 Cells; Obesity; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Processing, Post-Translational; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Estrogen; Receptors, Leptin; Signal Transduction; src-Family Kinases; Up-Regulation; Vascular Endothelial Growth Factor A

2014
Differential gene expression in ERα-positive and ERα-negative breast cancer cells upon leptin stimulation.
    Endocrine, 2013, Volume: 44, Issue:2

    In postmenopausal women, adipositas represents a serious risk factor for cancer development and progression. White adipose tissue secretes the 16 kDa hormone leptin which plays a key role in the regulation of appetite and metabolism. An increasing number of reports indicate that leptin also interferes with signal transduction pathways implicated in the development of breast cancer. In our previous study, we identified the estrogen receptor alpha (ERα) as a relevant enhancer of leptin-induced signal transduction leading to transactivation of signal transducer and activator of transcription 3 (Stat3). The purpose of this study is the investigation of specific target gene expression in response to leptin-mediated Stat3 signaling. We performed a comprehensive microarray analysis of ERα-positive and ERα-negative MDA-MB-231 cells upon leptin treatment and identified 49 genes which showed a significant ERα-dependent regulation in leptin-treated MDA-MB-231 cells. There was no intersection with genes which were merely up- or downregulated by ERα expression and only 9 and 11 genes overlapping targets which were regulated by leptin stimulation either in ERα-expressing or ERα-negative MDA-MB-231 cells, respectively. To demonstrate the specificity, expression of three target genes was validated by quantitative real-time PCR. In conclusion, these data imply that leptin can induce a different set of target genes dependent on ERα expression, which might contribute to the development and progression of cancer diseases.

    Topics: Breast Neoplasms; Estrogen Receptor alpha; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leptin; Microarray Analysis; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Transcriptome; Tumor Cells, Cultured

2013
Prediagnostic leptin, adiponectin, C-reactive protein, and the risk of postmenopausal breast cancer.
    Cancer prevention research (Philadelphia, Pa.), 2013, Volume: 6, Issue:3

    Obesity has been associated with an increased risk of postmenopausal breast cancer. Adipokines and systemic inflammation have been hypothesized to underlie this association. In a case-control study nested within the Multiethnic Cohort, conditional logistic regression was used to calculate the ORs and 95% confidence intervals (CI) for postmenopausal breast cancer associated with prediagnostic levels of serum leptin, adiponectin, the leptin:adiponectin ratio, and C-reactive protein (CRP). The 706 cases and 706 controls were matched on ethnicity, location (Hawaii or Los Angeles), birth year, date and time of blood draw, hours fasting before blood draw, and hormone replacement therapy use at blood draw. Higher circulating levels of leptin [ORQ4 vs. Q1, 1.94 (1.37-2.75); Ptrend ≤ 0.001), the leptin:adiponectin ratio [OR, 1.91 (1.36-2.68); Ptrend = 0.005], and CRP [OR, 1.41 (1.01-1.96); Ptrend = 0.014] were associated with an increased risk of postmenopausal breast cancer. The positive associations for these markers remained after adjustment for body mass index (BMI). No associations were detected for adiponectin. These data suggest that adipokines and systemic inflammation may be associated with the risk of postmenopausal breast cancer independently of BMI. Further prospective studies examining the role of adipokines and inflammatory processes in the etiology of postmenopausal breast cancer are warranted. Cancer Prev Res; 6(3); 188-95. ©2013 AACR.

    Topics: Adiponectin; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Female; Humans; Leptin; Postmenopause; Risk Factors

2013
Hyperresistinemia is associated with postmenopausal breast cancer.
    Menopause (New York, N.Y.), 2013, Volume: 20, Issue:8

    The constellation of obesity, insulin resistance, and serum adipocytokine levels is associated with the risk and prognosis of postmenopausal breast cancer (PBC). Altered secretion of resistin may underlie the association between overweight/obesity and PBC. We thus explored the association of serum resistin with PBC, taking into account established risk factors, including adipokines and anthropometric, metabolic, and inflammatory markers.. In a case-control study, we studied 102 postmenopausal women with pathologically confirmed, incident invasive breast cancer and 102 control participants matched on age and time of diagnosis between 2003 and 2010 at the Veterans' Administration General Hospital of Athens (NIMTS Hospital). Serum resistin, adiponectin, leptin, metabolic (homeostasis model assessment score of insulin resistance) and inflammatory (tumor necrosis factor-α, interleukin-6, and high-sensitivity C-reactive protein) parameters, and tumor markers (carcinoembryonic antigen and CA 15-3) were determined.. The mean serum resistin level was significantly higher in case participants than in control participants (P < 0.001) in both univariate and multivariable analyses, adjusting for age, date of diagnosis, education, family history of cancer, use of exogenous hormones, alcohol consumption, smoking status, physical activity, reproductive markers, metabolic markers, anthropometric (body mass index and weight circumference) markers, inflammatory markers, and adipokines (odds ratio, 1.17; 95% CI, 1.03-1.34; P = 0.02). In case participants, resistin level correlated significantly with tumor markers and inflammatory parameters, but not with metabolic and anthropometric variables.. Further prospective, longitudinal, and mechanistic studies are needed to determine whether hyperresistinemia is involved in the development of PBC or reflects changes during PBC progression and therefore could be used as a biomarker for PBC. Targeting resistin inhibition could be an effective therapeutic strategy in breast cancer by down-regulating the inflammatory microenvironment in breast tissue.

    Topics: Adipokines; Aged; Aged, 80 and over; Biomarkers; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; C-Reactive Protein; Case-Control Studies; Female; Humans; Inflammation; Insulin Resistance; Interleukin-6; Leptin; Middle Aged; Obesity; Postmenopause; Prognosis; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

2013
Breast cancer and obesity: in vitro interferences between adipokines and proangiogenic features and/or antitumor therapies?
    PloS one, 2013, Volume: 8, Issue:3

    Obesity is now considered as a risk factor for breast cancer in postmenopausal women. Adipokine levels are modulated in obesity, and may play a role in carcinogenesis. Moreover, obesity increases risk of cancer mortality. Here, we hypothesized that this increase could be due to a modification in angiogenesis, capital event in the development of metastases, and/or in effectiveness of cancer treatments. To test these assumptions, following a same experimental design and simultaneously the effects of leptin and adiponectin on angiogenesis were investigated, and the impact of hyperleptinemia on anticancer drug effectiveness was measured in physiological and obesity situations. Focusing on angiogenesis, the proliferation of endothelial cells (HUVEC), which expressed leptin and adiponectin receptors, was stimulated by leptin and inhibited by adiponectin. Both adipokines globally reduced apoptosis and caspase activity. Leptin increased migration whereas adiponectin decreased migration, and leptin enhanced the area of the tubes formed by HUVEC cells while adiponectin inhibited their formation. MCF7 and MDA-MB-231 cells treated with leptin secreted more VEGF than untreated cells, whereas adiponectin treatment inhibited VEGF secretion. Finally, MCF7 cells pre-treated with leptin were more invasive than untreated cells. This effect was not reproduced in MDA-MB-231 cells. In the MCF7 breast cancer cell line, leptin could induce cell proliferation and reduced the efficacy of all breast cancer therapies (tamoxifen, 5-fluorouracil, taxol and vinblastin). These results suggest that, in obesity situation, leptin- in contrast to adiponectin - may promote tumor invasion and angiogenesis, leading to metastases 'apparition, and reduce treatment efficacy, which could explain the increased risk of cancer mortality in cases of overweight. The evidence suggests adipokines influence breast cancer issue and could play a significant role, especially in obese patients for which hyperleptinemia, hypoadiponectinemia and increased metastatic potential are described.

    Topics: Adiponectin; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Human Umbilical Vein Endothelial Cells; Humans; Leptin; Neoplasm Invasiveness; Neoplasm Proteins; Neovascularization, Pathologic; Obesity; Receptors, Leptin; Vascular Endothelial Growth Factor A

2013
Plasma leptin levels, LEPR Q223R polymorphism and mammographic breast density: a cross-sectional study.
    The International journal of biological markers, 2013, Jun-28, Volume: 28, Issue:2

    Obesity is associated with breast cancer in post-menopausal women, and breast density is a marker of breast cancer risk. Leptin is produced by the adipose tissue, acts through receptors that are polymorphic in nature, and is considered a cancer growth factor. The relationship between body mass index, leptin, leptin receptors and breast density is not well studied. A cross-sectional analysis in 392 post-menopausal healthy women was conducted; participants provided permission to obtain copies of their most recent screening mammogram. Non-fasting plasma leptin levels were determined using a commercially available leptin ELISA kit. Analysis of the Q223R genotypes of the LEPR gene were performed by PCR followed by restriction fragment length polymorphism analysis using DNA extracted from buffy coat samples. A statistically significant positive relationship was observed between leptin levels and body mass index (p<0.0001); leptin was significantly positively associated with mammography total breast area and non-dense breast area (p<0.0001), while it was inversely associated with percent breast density (p<0.0001). Leptin levels varied across the LEPR Q223R polymorphism, and were higher in women homozygous for the AA variant. Percent breast density decreased across the LEPR Q223R genotype, with lower percent density in women with the AA genotype. When dense area was considered according to quartiles of leptin and stratified by LEPR Q223R, a significant inverse trend between leptin levels and dense breast area was observed only among women with the G/G genotype (p-trend<0.001). After adjustment for possible confounders, leptin levels were significantly inversely associated with percent breast density (p=0.01). A significant interaction between body mass index and leptin levels on percent breast density was observed (p=0.03). These findings suggest that the association between leptin and breast density may vary by LEPR Q223R genotype, and that body mass index and leptin may act in an interactive way in determining breast density.

    Topics: Adult; Aged; Biomarkers, Tumor; Breast Density; Breast Neoplasms; Cross-Sectional Studies; Early Detection of Cancer; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Mammary Glands, Human; Middle Aged; Polymorphism, Single Nucleotide; Receptors, Leptin

2013
Adipocytokines, inflammation, and breast cancer risk in postmenopausal women: a prospective study.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013, Volume: 22, Issue:7

    Obesity is a known risk factor for postmenopausal breast cancer; it has been postulated that adipocytokines may mediate this association. We explored the relationship between three markers altered by obesity: leptin, adiponectin, and soluble tumor necrosis factor receptor 2 (sTNF-R2), an inflammatory marker, with breast cancer risk in postmenopausal women. A nested case-control study of postmenopausal women was conducted within CLUE II, a prospective population-based cohort. Baseline plasma levels of leptin, adiponectin, and sTNF-R2 were assayed in 272 female breast cancer cases and 272 controls matched on age, date, and hour of blood draw. Conditional logistic regression was used to estimate matched odds ratios (OR) and 95% confidence intervals (CI). sTNF-R2 and leptin were independently positively associated with breast cancer risk in adjusted models. The OR for breast cancer comparing the highest to lowest tertile was 2.44 (95% CI: 1.30-4.58) for sTNF-R2 and 1.98 (95% CI: 1.20-3.29) for leptin. While higher levels of adiponectin were protective (OR for the lowest tertile = 1.63; 95% CI: 1.02-2.60), there was no dose response. A 20% reduction in the breast cancer risk associated with overweight/obesity was observed when sTNF-R2 alone was included in multivariable models. Including both sTNF-R2 and adiponectin in the models resulted in a 29% reduction in the OR. Adipocytokines and sTNF-R2 are important factors in the etiology of postmenopausal breast cancer due to adiposity. This study informs our understanding of the relationship between obesity, inflammation, and postmenopausal breast cancer and identifies potential biomarkers.

    Topics: Adipokines; Breast Neoplasms; Case-Control Studies; Cohort Studies; Female; Humans; Inflammation; Leptin; Middle Aged; Nitriles; Obesity; Postmenopause; Prospective Studies; Risk Factors

2013
Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index.
    The Journal of clinical endocrinology and metabolism, 2013, Volume: 98, Issue:7

    Endogenous sex hormones are risk factors for postmenopausal breast cancer. A potential route for favorable hormonal modification is weight loss.. The objective of the study was to measure change in plasma estradiol and testosterone levels in postmenopausal women in relation to change in body mass index (BMI) and plasma leptin.. The setting was a cohort study of over 100,000 female volunteers from the general population, United Kingdom.. The participants were a sample of 177 postmenopausal women aged over 45 years who provided blood samples during 2004-2005 and again during 2010-2011.. Outcomes were percentage change in plasma estradiol and testosterone levels per 1 kg/m² change in BMI and per 1 ng/mL change in plasma leptin.. Among women with reduction in BMI, estradiol decreased 12.7% (95% confidence interval: [6.4%, 19.5%]; P < .0001) per kg/m² and among women with increased BMI estradiol increased 6.4% [0.2%, 12.9%] (P = .042). The corresponding figures for testosterone were 10.7% [3.0%, 19.0%] (P = .006) and 1.9% [-5.4%, 9.7%] (P = .61) per kg/m². For women with decreases and increases in leptin, estradiol decreased by 3.6% [1.3%, 6.0%] (P = .003) per ng/mL and increased by 1.7% [-0.3%, 3.6%] (P = .094), respectively. The corresponding figures for testosterone were 4.8% [2.0%, 7.8%] (P = .009) and 0.3% [-2.0%, 2.6%] (P = .82) per ng/mL.. In postmenopausal women, changes in BMI and plasma leptin occurring over several years are associated with changes in estradiol and testosterone levels. The results suggest that fat loss by an individual can result in substantial decreases in postmenopausal estradiol and testosterone levels and provides support for weight management to lessen breast cancer risk.

    Topics: Adipose Tissue; Aged; Body Mass Index; Breast Neoplasms; Cohort Studies; Down-Regulation; Estradiol; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Overweight; Postmenopause; Risk Factors; Testosterone; United Kingdom; Up-Regulation; Weight Gain; Weight Loss

2013
Peritumoral expression of adipokines and fatty acids in breast cancer.
    Annals of surgical oncology, 2013, Volume: 20 Suppl 3

    Adipokines in the tumor microenvironment may contribute to cancer growth. We hypothesized that peritumoral fat can be a source of lipid-derived energy for tumors by increasing adipose triglyceride lipase (ATGL)-mediated lipolysis and down-regulating a negative regulator of adipogenesis, pigment epithelium-derived factor (PEDF).. In a pilot study, tissue from mastectomies (n = 19) was collected from sites both adjacent (peritumoral) and distant to the tumor for comparison of ATGL, PEDF, and leptin expression levels using immunohistochemistry. Statistical analysis was performed by Student's t test to determine significance.. Mean tumor size was 2.4 cm, and 10 (59 %) patients had tumor-positive nodes. Mean body mass index (BMI) was 28.1 kg/m(2). ATGL expression was significantly increased in obese patients (BMI ≥ 30 kg/m(2)) compared with the nonobese group (P < 0.04). Leptin expression was increased in the peritumoral stroma of obese patients compared with distant sites (P = 0.03). Peritumoral PEDF and the leptin/PEDF ratio were significantly affected by tumor size and node status. Tumors ≥ 2 cm had lower peritumoral stromal expression of PEDF than tumors <2 cm (P = 0.01). In node-positive cases, expression of PEDF was significantly decreased in the peritumoral stroma compared with node-negative cases (1.22 vs. 1.80, P < 0.04). The leptin/PEDF ratio was markedly elevated in the peritumoral region of node-positive cases versus node-negative cases (2.17 vs. 1.18, P < 0.001).. Peritumoral expression of adipokines was altered in both obesity and more advanced breast tumors, suggesting a role for adipokines in enhancing tumor growth. Future studies should focus on the use of adipokines as biomarkers.

    Topics: Adipokines; Adipose Tissue; Adult; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Cell Proliferation; Eye Proteins; Fatty Acids; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; Leptin; Lipase; Lymphatic Metastasis; Mastectomy; Middle Aged; Neoplasm Staging; Nerve Growth Factors; Obesity; Pilot Projects; Prognosis; Serpins; Survival Rate; Tumor Cells, Cultured

2013
Insulin and leptin levels in obese patients with and without breast cancer.
    Clinical breast cancer, 2013, Volume: 13, Issue:6

    Leptin has been associated with progression and poor survival in BC. Moreover, it is still controversial as to whether the effect of leptin depends only on its correlation with body mass index (BMI), or could be a direct role of adipokine in the development of BC. The aim of this study was to identify if there was a difference between serum leptin levels and insulin in obese patients with and without BC.. A cross-sectional study was made in 156 women, a group of 78 with obesity and BC and 78 with obesity without BC. When subjects agreed to participate, written informed consent was obtained from all subjects. Biochemical variables such as glucose, triglycerides, high-density and low-density lipoprotein, cholesterol, insulin, and leptin were measured and homeostasis model assessment (HOMA-IR) was calculated.. The age, number of parities, glucose, HOMA-IR, and leptin were significantly different at P < .05.. Serum leptin levels and leptin/BMI ratio were statistically significantly increased in patients with BC.

    Topics: Blood Glucose; Body Mass Index; Breast Neoplasms; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Insulin; Insulin Resistance; Leptin; Middle Aged; Obesity; Prognosis

2013
Obesity associated alterations in the biology of adipose stem cells mediate enhanced tumorigenesis by estrogen dependent pathways.
    Breast cancer research : BCR, 2013, Volume: 15, Issue:5

    Obesity has been associated with increased incidence and mortality of breast cancer. While the precise correlation between obesity and breast cancer remains to be determined, recent studies suggest that adipose tissue and adipose stem cells (ASCs) influence breast cancer tumorigenesis and tumor progression.. Breast cancer cells lines were co-cultured with ASCs (n = 24), categorized based on tissue site of origin and body mass index (BMI), and assessed for enhanced proliferation, alterations in gene expression profile with PCR arrays, and enhanced tumorigenesis in immunocompromised mice. The gene expression profile of ASCs was assess with PCR arrays and qRT-PCR and confirmed with Western blot analysis. Inhibitory studies were conducted by delivering estrogen antagonist ICI182,780, leptin neutralizing antibody, or aromatase inhibitor letrozole and assessing breast cancer cell proliferation. To assess the role of leptin in human breast cancers, Oncomine and Kaplan Meier plot analyses were conducted.. ASCs derived from the abdominal subcutaneous adipose tissue of obese subjects (BMI > 30) enhanced breast cancer cell proliferation in vitro and tumorigenicity in vivo. These findings were correlated with changes in the gene expression profile of breast cancer cells after co-culturing with ASCs, particularly in estrogen receptor-alpha (ESR1) and progesterone receptor (PGR) expression. Analysis of the gene expression profile of the four groups of ASCs revealed obesity induced alterations in several key genes, including leptin (LEP). Blocking estrogen signaling with ICI182,780, leptin neutralizing antibody, or letrozole diminished the impact of ASCs derived from obese subjects. Women diagnosed with estrogen receptor/progesterone receptor positive (ER+/PR+) breast cancers that also expressed high levels of leptin had poorer prognosis than women with low leptin expression.. ASCs isolated from the abdomen of obese subjects demonstrated increased expression of leptin, through estrogen stimulation, which increased breast cancer cell proliferation. The results from this study demonstrate that abdominal obesity induces significant changes in the biological properties of ASCs and that these alterations enhance ER+/PR+ breast cancer tumorigenesis through estrogen dependent pathways.

    Topics: Adipocytes; Animals; Aromatase; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Coculture Techniques; Cyclin-Dependent Kinase Inhibitor p16; Estrogen Receptor alpha; Estrogens; Female; Gene Expression Profiling; Glutathione S-Transferase pi; Humans; Intercellular Signaling Peptides and Proteins; Leptin; MCF-7 Cells; Membrane Proteins; Mice; Obesity; Receptors, Estrogen; Receptors, Progesterone; Signal Transduction; Stem Cells; Tumor Burden

2013
Gut peptide profile and chemotherapy-associated dyspepsia syndrome in patients with breast cancer undergoing FEC60 chemotherapy.
    Anticancer research, 2013, Volume: 33, Issue:11

    The association of motilin, ghrelin, leptin, gastrin, pepsinogen (PG) I and II with cancer chemotherapy-associated dyspepsia syndrome (CADS) was investigated in 35 patients with breast cancer receiving first cycle of 5-fluorouracil, cyclophosphamide, epirubicin (FEC60) chemotherapy.. The onset of dyspeptic symptoms on days 3 and 10 after chemotherapy identified patients with and without CADS. Gastrointestinal symptoms were scored with the Gastrointestinal Symptom Scoring Rate (GSRS) questionnaire. Gastrointestinal peptides were evaluated by enzyme-linked immunosorbent assay.. Twenty-one patients (60%) had CADS. The area under the curve (AUC) of ghrelin was higher, whereas that of PGI, PGII and motilin were lower in patients with CADS compared to those without. In patients with CADS, the AUC of PGI and PGII negatively correlated with the GSRS indigestion cluster.. Impairment of gastrointestinal motility suggested by low motilin concentrations and mucosal damage mirrored by an increase of ghrelin seem to be involved in the onset of CADS in patients during chemotherapy for breast cancer.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Chemotherapy, Adjuvant; Cyclophosphamide; Dyspepsia; Epirubicin; Female; Fluorouracil; Follow-Up Studies; Gastrins; Gastrointestinal Motility; Gastrointestinal Tract; Ghrelin; Humans; Leptin; Middle Aged; Motilin; Neoplasm Staging; Pepsinogen A; Pepsinogen C; Peptide Fragments; Prognosis; Prospective Studies; Syndrome

2013
[The effect of leptin and its mechanisms on the migration and invasion of human breast cancer MCF-7 cells].
    Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2013, Volume: 29, Issue:12

    To investigate the effect and the relevant molecular mechanisms of leptin on the migration and invasion of human breast cancer MCF-7 cells.. The expression of OB-R in MCF-7 cells was measured by RT-PCR and Western blotting. The effects of leptin (100 ng/mL) on the the phosphorylation of a few key cell signaling proteins, p-ERK1/2, p-STAT3, p-AKT in MCF-7 cells were examined by Western blotting. Cell scratch assay and Transwell(TM); assay were utilized to measure the effects of leptin on the migration and invasion capability of MCF-7 cells, respectively. The effects of leptin on the mRNA and protein expression of matrix metalloproteinas 9 (MMP-9) and transforming growth factor β (TGF-β) were measured by RT-PCR and Western blotting.. Both OB-Rb and OB-Rt were expressed in MCF-7 cells. This indicated that leptin may have significant activities in MCF7 cells. Indeed, leptin increased the phosphorylation of p-ERK1/2, p-STAT3, and p-AKT in MCF-7 cells (P < 0.05). Further, leptin promoted migration and invasion of MCF-7 cells, which were attenuated by the JAK/STAT inhibitor AG490 (50 μmol/L), and the PI3K/AKT inhibitor LY294002 (10 μmol/L) (P < 0.05). Similarly, leptin also increased the mRNA and protein expression of MMP-9 and TGF-β, and these effects were blocked by AG490 and LY294002 as well (P < 0.05).. Leptin promoted the migration and invasion capabilities of MCF-7 cells. These activities may be achieved by the upregulation of MMP-9 and TGF-β through JAK/STAT and PI3K/AKT signaling pathways.

    Topics: Breast Neoplasms; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Leptin; Matrix Metalloproteinase 9; MCF-7 Cells; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Invasiveness; Phosphoproteins; Proto-Oncogene Proteins c-akt; Receptors, Leptin; STAT3 Transcription Factor; Transforming Growth Factor beta

2013
Serum leptin level and waist-to-hip ratio (WHR) predict the overall survival of metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs).
    Breast cancer (Tokyo, Japan), 2013, Volume: 20, Issue:2

    Our objective was to determine whether serum leptin levels and obesity-related factors could affect outcome for metastatic breast cancer (MBC) patients treated with aromatase inhibitors (AIs).. Sixty MBC patients treated with first line hormonal therapy were enrolled in this study.. Median age was 51 years (range 28-75). Median leptin level was 19400 pg/ml (1970-91900) and estradiol level 29.6 pg/ml (4.0-181.9). Factors associated with overall survival in univariate analysis were age and waist-to-hip ratio (WHR), whereas only WHR retained significance in the multivariate analysis. However, no factor was associated with progression-free survival. However, WHR was found to be a significant prognostic marker only if the leptin level was ≥19400 pg/ml (HR = 0.38; 95% CI: 0.16-0.91).. This study suggests that serum leptin levels and WHR together may serve as potential prognostic markers in MBC patients treated with AIs.

    Topics: Adult; Aged; Aromatase Inhibitors; Biomarkers, Tumor; Bone Neoplasms; Breast Neoplasms; Estradiol; Female; Follow-Up Studies; Humans; Leptin; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Estrogen; Receptors, Progesterone; Risk Factors; Soft Tissue Neoplasms; Survival Rate; Waist-Hip Ratio

2013
Leptin attenuates the anti-estrogen effect of tamoxifen in breast cancer.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2013, Volume: 67, Issue:1

    Leptin is a circulating peptide hormone, encoded by the obesity (ob) gene, acting as a regulator of food intake via hypothalamic-mediated effects. Recent studies have shown that leptin and leptin receptor (ObR) are involved in the carcinogenesis and development of breast cancer. In addition, functional cross talk between leptin and estrogen signaling has been registered. Here, we investigated the relation of leptin and ObR expression with survival in women with breast cancer treated with the anti-estrogen tamoxifen, and whether leptin can interfere with the estrogen receptor alpha (ERα) and the effect of tamoxifen in breast cancer cells.. The protein expression of leptin and ObR(b) in 114 breast cancer samples was evaluated by immunohistochemistry, quantified by Immunoreactivity Score (IRS) and correlated to survival and other clinicopathological features. The expression of ObR(b) in ERα positive MCF-7 breast cancer cells was examined by immunofluorescence and western blot. Leptin effect on cell proliferation was determined by MTT assay. The interference of leptin with tamoxifen on ERα degradation was studied by western blot and immunofluorescence. Effects of leptin on the transcriptional activity of ERα were explored using luciferase reporter assays.. Positive staining (Immunoreactivity Score, IRS≥1) of leptin and ObR isoform ObRb in breast cancer tissues were seen in 79.8% and 85.1% of patients respectively. In overall and in tamoxifen-treated breast cancer patients, leptin expression (IRS≥1) correlated with poor prognosis, (log-rank test, P=0.016, overall; P=0.031, tamoxifen-treated). Overexpressed ObRb was found by western blotting andimmunofluorescence in MCF-7 as well as in MDA-MB-231, T47D, and MDA-MB-435 cell lines. Tamoxifen (1000μM) significantly inhibited the proliferation of MCF-7 cells, degraded ERα and reduced ERα-dependent transcription from estrogen response element-containing promoter. On the contrary, simultaneous treatment with leptin (100ng/ml) significantly attenuated these effects, similar to the effects of estradiol.. Leptin correlated significantly with poor prognosis in overall and tamoxifen-treated breast cancer patients. Leptin interferes with the action of tamoxifen in MCF-7 cells, at least partly, through inducing increased nuclear expression of ERα. Thus, leptin may contribute to tamoxifen resistance and consequently, leptin suppression could be a novel way of circumventing resistance to anti-estrogen treatment.

    Topics: Antineoplastic Agents, Hormonal; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Estrogen Antagonists; Estrogen Receptor alpha; Female; Follow-Up Studies; Humans; Immunohistochemistry; Leptin; Middle Aged; Prognosis; Receptors, Leptin; Tamoxifen

2013
Leptin increases HER2 protein levels through a STAT3-mediated up-regulation of Hsp90 in breast cancer cells.
    Molecular oncology, 2013, Volume: 7, Issue:3

    Obesity condition confers risks to breast cancer development and progression, and several reports indicate that the adipokine leptin, whose synthesis and plasma levels increase with obesity, might play an important role in modulating breast cancer cell phenotype. Functional crosstalk occurring between leptin and different signaling molecules contribute to breast carcinogenesis. In this study, we show, in different human breast cancer cell lines, that leptin enhanced the expression of a chaperone protein Hsp90 resulting in increased HER2 protein levels. Silencing of Hsp90 gene expression by RNA interference abrogated leptin-mediated HER2 up-regulation. Leptin effects were dependent on JAK2/STAT3 activation, since inhibition of this signaling cascade by AG490 or ectopic expression of a STAT3 dominant negative abrogated leptin-induced HER2 and Hsp90 expressions. Functional experiments showed that leptin treatment significantly up-regulated human Hsp90 promoter activity. This occurred through an enhanced STAT3 transcription factor binding to its specific responsive element located in the Hsp90 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Analysis of HER2, Akt and MAPK phosphorylation levels revealed that leptin treatment amplified the responsiveness of breast cancer cells to growth factor stimulation. Furthermore, we found that long-term leptin exposure reduced sensitivity of breast cancer cells to the antiestrogen tamoxifen. In the same experimental conditions, the combined treatment of tamoxifen with the Hsp90 inhibitor 17-AAG completely abrogated leptin-induced anchorage-independent breast cancer cell growth. In conclusion, our results highlight, for the first time, the ability of the adipocyte-secreted factor leptin to modulate Hsp90/HER2 expressions in breast cancer cells providing novel insights into the molecular mechanism linking obesity to breast cancer growth and progression.

    Topics: Antineoplastic Agents, Hormonal; Breast; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Leptin; Promoter Regions, Genetic; Receptor, ErbB-2; STAT3 Transcription Factor; Tamoxifen; Up-Regulation

2013
Effects of PPARγ agonists on the expression of leptin and vascular endothelial growth factor in breast cancer cells.
    Journal of cellular physiology, 2013, Volume: 228, Issue:6

    The obesity hormone leptin has been implicated in breast cancer development. Breast cancer cells express the leptin receptor and are able to synthesize leptin in response to obesity-related stimuli. Furthermore, leptin is a positive regulator of vascular endothelial growth factor (VEGF) and high levels of both proteins are associated with worse prognosis in breast cancer patients. Peroxisome proliferator-activated receptor γ (PPARγ) ligands are therapeutic agents used in patient with Type 2 diabetes and obesity which have recently been studied for their potential anti-tumor effect. Here, we studied if these compounds, ciglitazone and GW1929, can affect the expression of leptin and VEGF in breast cancer cells. In MDA-MB-231 and MCF-7 breast cancer cells, treatment with submolar concentrations of ciglitazone and GW1929 elevated the expression of leptin and VEGF mRNA and protein, and increased cell viability and migration. These effects coincided with increased recruitment of PPARγ to the proximal leptin promoter and decreased association of a transcriptional factor Sp1 with this DNA region.

    Topics: Benzophenones; Binding Sites; Breast Neoplasms; Cell Movement; Cell Survival; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Ligands; MCF-7 Cells; PPAR gamma; Promoter Regions, Genetic; RNA, Messenger; Sp1 Transcription Factor; Thiazolidinediones; Tyrosine; Vascular Endothelial Growth Factor A

2013
The tetrad BMI, leptin, leptin/adiponectin (L/A) ratio and CA 15-3 are reliable biomarkers of breast cancer.
    Journal of clinical laboratory analysis, 2013, Volume: 27, Issue:1

    Several studies have reported that leptin levels, the leptin/adiponectin (L/A) ratio and carbohydrate antigen (CA) 15-3 are especially elevated in breast cancer patients with high body mass index (BMI). The purpose of this study was to evaluate BMI, leptin, L/A ratio and CA 15-3 all together as reliable biomarkers for breast cancer.. Serum levels of leptin, adiponectin and CA 15-3, as well as anthropometric and biochemical parameters were analysed in 88 female patients who participated in a mammography study. Predictive values of BMI, leptin, L/A ratio and CA 15-3 were determined with a 95% confidence interval.. Women were diagnosed with either breast cancer (n = 40) or benign breast lesions (n = 48). Among anthropometric parameters, age (P ≤ 0.001), weight (P ≤ 0.05) and waist circumference (P ≤ 0.02) were higher in patients with breast cancer than in patients without this pathology. The 75th percentile values for BMI, leptin, L/A ratio and CA 15-3 were 29.24 kg/m(2), 26.65 ng/ml, 2.37 and 18.45 IU, respectively. The suggested odds ratio for breast cancer patients with the values that were above the 75th percentile of the tetrad was 6.7 (0.7505-60.0665 confidence interval).. When the four variables were analysed together, a sensitivity of 83.3%, specificity of 80%, positive predictive value of 83.3% and negative predictive value of 80% were obtained. Results indicate that using the 75th percentile set points for BMI, leptin, L/A ratio and CA 15-3 together could offer a reliable approach to determine which women are at high risk for developing breast cancer.

    Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Cross-Sectional Studies; Female; Humans; Leptin; Middle Aged; Mucin-1; Neoplasm Staging; Prospective Studies; ROC Curve

2013
Integral role of PTP1B in adiponectin-mediated inhibition of oncogenic actions of leptin in breast carcinogenesis.
    Neoplasia (New York, N.Y.), 2013, Volume: 15, Issue:1

    The molecular effects of obesity are mediated by alterations in the levels of adipocytokines. High leptin level associated with obese state is a major cause of breast cancer progression and metastasis, whereas adiponectin is considered a "guardian angel adipocytokine" for its protective role against various obesity-related pathogenesis including breast cancer. In the present study, investigating the role of adiponectin as a potential inhibitor of leptin, we show that adiponectin treatment inhibits leptin-induced clonogenicity and anchorage-independent growth. Leptin-stimulated migration and invasion of breast cancer cells is also effectively inhibited by adiponectin. Analyses of the underlying molecular mechanisms reveal that adiponectin suppresses activation of two canonical signaling molecules of leptin signaling axis: extracellular signal-regulated kinase (ERK) and Akt. Pretreatment of breast cancer cells with adiponectin protects against leptin-induced activation of ERK and Akt. Adiponectin increases expression and activity of the physiological inhibitor of leptin signaling, protein tyrosine phosphatase 1B (PTP1B), which is found to be integral to leptin-antagonist function of adiponectin. Inhibition of PTP1B blocks adiponectin-mediated inhibition of leptin-induced breast cancer growth. Our in vivo studies show that adenovirus-mediated adiponectin treatment substantially reduces leptin-induced mammary tumorigenesis in nude mice. Exploring therapeutic strategies, we demonstrate that treatment of breast cancer cells with rosiglitazone results in increased adiponectin expression and inhibition of migration and invasion. Rosiglitazone treatment also inhibits leptin-induced growth of breast cancer cells. Taken together, these data show that adiponectin treatment can inhibit the oncogenic actions of leptin through blocking its downstream signaling molecules and raising adiponectin levels could be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.

    Topics: Adiponectin; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Leptin; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Invasiveness; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Rosiglitazone; Signal Transduction; Thiazolidinediones

2013
Favorable changes in serum estrogens and other biologic factors after weight loss in breast cancer survivors who are overweight or obese.
    Clinical breast cancer, 2013, Volume: 13, Issue:3

    Obesity is associated with an increased risk for recurrence and all-cause mortality in breast cancer survivors. Excess adiposity is associated with increased estrogen, insulin, and leptin, and with decreased sex hormone binding globulin (SHBG) concentrations, which may promote breast cancer progression and recurrence. This study aimed to assess the effects of weight loss on these factors.. Breast cancer survivors who were overweight or obese (n = 220) and who were enrolled in a weight loss intervention study provided baseline and follow-up blood samples and weight data. Serum estrogens, SHBG, insulin, and leptin were measured at baseline, 6 months, and 18 months.. Weight loss of ≥5% of initial weight decreased leptin and insulin compared with those who did not achieve that amount of weight loss (P < .0001). Weight loss also increased SHBG at 6 and 18 months (P < .01). Postmenopausal women who lost ≥5% of body weight at 6 months had lower estrone (P = .02), estradiol (P = .002), and bioavailable estradiol (P = .001) concentrations than women who did not lose at least 5% of body weight, and weight loss at 18 months was significantly related to a change in serum bioavailable estradiol concentration (P = .02).. Favorable changes in estrogens, SHBG, insulin, and leptin were observed in association with weight loss in these women who were overweight or obese and who had been diagnosed and treated for breast cancer. Weight loss appears to have favorable effects on hormonal and biologic factors associated with increased risk for recurrence and poorer prognosis.

    Topics: Aged; Biomarkers; Breast Neoplasms; Estrogens; Female; Humans; Insulin; Leptin; Middle Aged; Overweight; Sex Hormone-Binding Globulin; Weight Loss

2013
Leptin upregulates tissue factor expression in human breast cancer MCF-7 cells.
    Thrombosis research, 2012, Volume: 129, Issue:5

    Obesity is a risk factor for both cardiovascular disease and cancer development. Leptin, a cytokine produced by adipose tissue, controls different processes in peripheral tissues, including cancer development and thrombotic disorders in patients with a variety of clinical disorders. Tissue factor (TF), the trigger of blood clotting, is abundant in the adipose tissue. Since TF, often expressed by cancer cells, is considered a hallmark of cancer progression, we investigated whether leptin could modulate TF in the human metastatic breast carcinoma cell line MCF-7.. MCF-7 cells were incubated with or without the different reagents at 37 °C. At the end of incubation, cells were tested for procoagulant activity by a one-stage clotting assay, TF and TNF-α antigen levels and mRNA by ELISA and real-time RT-PCR, respectively. Leptin receptor was studied by FACS.. Both TF activity and antigen constitutively expressed by MCF-7 were significantly increased by leptin in a dose-dependent fashion. TF mRNA levels were also enhanced indicating that leptin exerts its effect at the transcription level. The effect of leptin was specific and required binding to its receptor (Ob-R), which was found on the surface of the cells, since antibodies against leptin and Ob-R completely prevented TF expression upregulation. In addition, leptin enhanced both TNF-α mRNA synthesis and secretion from MCF7. An anti-TNF-α MoAb completely abolished the leptin-induced TF expression.. These data support the hypothesis that leptin, by its upregulation of TF, possibly mediated by TNF-α synthesis, may contribute to processes underlying both cancer and vascular cell disorders.

    Topics: Breast Neoplasms; Cardiovascular Diseases; Cell Line, Tumor; Female; Humans; Leptin; Obesity; Receptors, Leptin; Thromboplastin; Up-Regulation

2012
Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2012, Jan-10, Volume: 30, Issue:2

    To investigate patterns of prognostic associations over time of insulin- and obesity-related variables measured at diagnosis of early breast cancer (BC), focusing on whether the prognostic associations with distant recurrence and death changed over time.. Five hundred thirty-five nondiabetic women with T1-3, N0-1, M0 invasive BC diagnosed from 1989 to 1996 were included in the study. Insulin-related variables included fasting insulin, Homeostasis Model Assessment, C-peptide, and glucose. Obesity-related variables included weight, body mass index (BMI), waist and hip circumference, and leptin. Correlations were examined using the Pearson correlation coefficient and prognostic associations using the Cox model.. There was evidence that associations of baseline insulin-related variables with distant recurrence and death were not constant over time; univariable adverse prognostic associations were significant only during the first 5 years (eg, insulin quartile 4 v 1: hazard ratio [HR], 2.32; 95% CI, 1.39 to 3.86; P < .001 for distant disease-free survival [DDFS]; and HR, 2.85; 95% CI, 1.48 to 5.50; P = .002 for overall survival [OS], with little attenuation of this pattern in multivariable analyses). In contrast, obesity-related variables (BMI, weight, leptin) exerted significant adverse univariable associations that were constant over time (eg, BMI quartile 4 v 2: HR, 1.40; 95% CI, 1.07 to 1.82 for DDFS; P = .014; and HR, 1.50; 95% CI, 1.16 to 1.93; P < .001 for OS); prognostic associations of leptin remained significant in multivariable analyses.. Baseline insulin- and obesity-related variables exert different patterns of prognostic associations over time in early BC.

    Topics: Aged; Aged, 80 and over; Body Mass Index; Breast Neoplasms; Disease-Free Survival; Female; Humans; Insulin; Leptin; Middle Aged; Neoplasm Staging; Obesity; Prognosis; Risk Factors

2012
Programmed cell death 4 inhibits leptin-induced breast cancer cell invasion.
    Oncology reports, 2012, Volume: 27, Issue:3

    Obesity is a significant risk factor for post-menopausal women to develop and die from breast cancer. Leptin, an adipokine is produced in high levels in obese individuals, and its receptor is overexpressed in breast tumors and lymph node metastases. Previously, we demonstrated that leptin stimulates breast cancer cell invasion, which is correlated with breast cancer metastasis. Programmed cell death 4 (PDCD4) has been shown to block cancer cell invasion. However, whether PDCD4 blocks leptin-induced breast cancer cell invasion is not known. Here, we report the novel findings that leptin failed to induce invasion in MCF-7 breast cancer cells overexpressing PDCD4 (MCF-7/PDCD4). Tissue inhibitor of metalloproteinase-2 (TIMP-2) was essential to the anti-invasive effect of PDCD4, as leptin stimulated the invasion of MCF-7/PDCD4 cells pretreated with TIMP-2 siRNA. Furthermore, TIMP-2 knockdown allowed leptin to augment phosphorylation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3, but not that of Jun N-terminal kinases. These data indicate that PDCD4 utilizes TIMP-2 to exert its anti-invasive effect by suppressing leptin-induced activation of extracellular signal-regulated kinases 1,2 and signal transducer and activator of transcription 3. Novel therapeutic strategies aiming at enhancing PDCD4 expression in breast tumors may be able to stop obesity-related breast tumor progression and prolong the life of patients.

    Topics: Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Line, Tumor; Female; Gene Knockdown Techniques; Humans; JNK Mitogen-Activated Protein Kinases; Leptin; MAP Kinase Signaling System; Neoplasm Invasiveness; Phosphorylation; RNA-Binding Proteins; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Tissue Inhibitor of Metalloproteinase-2; Transfection

2012
Leptin-induced epithelial-mesenchymal transition in breast cancer cells requires β-catenin activation via Akt/GSK3- and MTA1/Wnt1 protein-dependent pathways.
    The Journal of biological chemistry, 2012, Mar-09, Volume: 287, Issue:11

    Perturbations in the adipocytokine profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether leptin is involved in epithelial-mesenchymal transition (EMT). Here, we provide molecular evidence that leptin induces breast cancer cells to undergo a transition from epithelial to spindle-like mesenchymal morphology. Investigating the downstream mediator(s) that may direct leptin-induced EMT, we found functional interactions between leptin, metastasis-associated protein 1 (MTA1), and Wnt1 signaling components. Leptin increases accumulation and nuclear translocation of β-catenin leading to increased promoter recruitment. Silencing of β-catenin or treatment with the small molecule inhibitor, ICG-001, inhibits leptin-induced EMT, invasion, and tumorsphere formation. Mechanistically, leptin stimulates phosphorylation of glycogen synthase kinase 3β (GSK3β) via Akt activation resulting in a substantial decrease in the formation of the GSK3β-LKB1-Axin complex that leads to increased accumulation of β-catenin. Leptin treatment also increases Wnt1 expression that contributes to GSK3β phosphorylation. Inhibition of Wnt1 abrogates leptin-stimulated GSK3β phosphorylation. We also discovered that leptin increases the expression of an important modifier of Wnt1 signaling, MTA1, which is integral to leptin-mediated regulation of the Wnt/β-catenin pathway as silencing of MTA1 inhibits leptin-induced Wnt1 expression, GSK3β phosphorylation, and β-catenin activation. Furthermore, analysis of leptin-treated breast tumors shows increased expression of Wnt1, pGSK3β, and vimentin along with higher nuclear accumulation of β-catenin and reduced E-cadherin expression providing in vivo evidence for a previously unrecognized cross-talk between leptin and MTA1/Wnt signaling in epithelial-mesenchymal transition of breast cancer cells.

    Topics: beta Catenin; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cadherins; Cell Line, Tumor; Cell Nucleus; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Histone Deacetylases; Humans; Leptin; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrimidinones; Repressor Proteins; Trans-Activators; Vimentin; Wnt Signaling Pathway; Wnt1 Protein

2012
Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells.
    Cancer research, 2012, Mar-15, Volume: 72, Issue:6

    Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type (WT) and K303R mutant estrogen receptor-α (ERα)-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ERα hyperactive receptor than WT-ERα-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ERα compared with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and "educated" CAFs that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer-stromal cell communication may represent an effective strategy for targeted therapy of breast cancer.

    Topics: Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epidermal Growth Factor; Estrogen Receptor alpha; Female; Fibroblasts; Gene Expression Profiling; Humans; Leptin; Neoplasm Invasiveness; Receptors, Leptin; Signal Transduction; Stromal Cells

2012
Effects of exogenous human leptin on heat shock protein 70 expression in MCF-7 breast cancer cells and breast carcinoma of nude mice xenograft model.
    Chinese medical journal, 2012, Volume: 125, Issue:4

    It is important to identify the multiple sites of leptin activity in obese women with breast cancer. In this study, we examined the effect of exogenous human leptin on heat shock protein 70 (HSP70) expression in MCF-7 human breast cancer cells and in a breast carcinoma xenograft model of nude mice.. We cultured MCF-7 human breast cancer cells and established nude mice bearing xenografts of these cells, and randomly divided them into experimental and control groups. The experimental group was treated with human leptin, while the control group was treated with the same volume of normal saline. A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed to quantify the mRNA expression of HSP70 in the MCF-7 human breast cancer cells and in tumor tissues. Western blotting analysis was applied to quantify the protein expression of HSP70 in the MCF-7 cells. Immunohistochemical staining was done to assess the positive rate of HSP70 expression in the tumor tissues.. Leptin activated HSP70 in a dose-dependent manner in vitro: leptin upregulated significantly the expression of HSP70 at mRNA and protein levels in MCF-7 human breast cancer cells (P < 0.001). There was no significant difference in expression of HSP70 mRNA in the implanted tumors between the leptin-treated group and the control group (P > 0.05). Immunohistochemical staining revealed no significant difference in tumor HSP70 expression between the leptin-treated group and the control group (P > 0.05).. A nude mouse xenograft model can be safely and efficiently treated with human leptin by subcutaneous injections around the tumor. HSP70 may be target of leptin in breast cancer. Leptin can significantly upregulate the expression of HSP70 in a dose-dependent manner in vitro.

    Topics: Animals; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Female; HSP70 Heat-Shock Proteins; Humans; Immunohistochemistry; Leptin; Mice; Mice, Nude; Real-Time Polymerase Chain Reaction; Xenograft Model Antitumor Assays

2012
Polymorphisms in adiposity-related genes are associated with age at menarche and menopause in breast cancer patients and healthy women.
    Human reproduction (Oxford, England), 2012, Volume: 27, Issue:7

    Is there any effect of genetic polymorphisms in adiposity-related genes on the timing of menarche and menopause and the total duration of menstruation among Korean women?. Our results suggest that the adiposity-related genes LEP, LEPR and PPARγ may play a role in the onset and cessation of menstruation, and the total duration of menstruation.. Previous candidate-gene approaches have mainly presented the results for genes related to the estrogen metabolism pathway. Most genes of interest that participate in steroid-hormone metabolism, such as estrogen receptor α and estrogen receptor β, have been associated with age at menarche and menopause. This study shows the possibility that adiposity-related genes also influence the duration of menstruation.. We recruited 400 breast cancer patients and 452 healthy participants from a case-control study at the Center for Breast Cancer, National Cancer Center in Korea. Ten single nucleotide polymorphisms (SNPs) in the leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma (PPARγ) genes were investigated to evaluate their possible effects on menstruation. Associations between SNPs and age at menarche, age at menopause and duration of menstruation were evaluated.. Four SNPs (rs2167270 of LEP, rs7602 of LEPR and rs4684846 and rs3856806 of PPARγ) were associated with late menarche (≥ 17-year-old). Four SNPs (rs2167270 of LEP and rs1801282, rs2120825, and rs3856806 of PPARγ) were associated with early menopause (<40-year-old) among post-menopausal women. In logistic regression models with covariate adjustment, women with the GG genotype of rs7602 (LEPR) had a higher risk for late menarche [odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.01-3.31] compared with their counterparts carrying the GA or AA genotypes. In addition, the GG genotype of rs2167270 (LEP) was inversely associated with a duration of menstruation of <30 years (OR = 0.59, 95% CI = 0.31-1.00) compared with the GA or AA genotypes. BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS: We obtained information on the age at menarche and menopause from self-administered questionnaires, and some participants might have had difficulty in remembering their age at menarche and menopause. However, this is a non-differential misclassification and should not appreciably affect the interpretation of the results of this study.

    Topics: Adiposity; Adolescent; Adult; Aged; Breast Neoplasms; Case-Control Studies; Female; Genotype; Humans; Korea; Leptin; Menarche; Menopause; Middle Aged; Polymorphism, Genetic; Polymorphism, Single Nucleotide; PPAR gamma; Receptors, Leptin; Risk

2012
Associations of adipokines & insulin resistance with sex steroids in patients with breast cancer.
    The Indian journal of medical research, 2012, Volume: 135, Issue:4

    Several studies have suggested an important, but conflicting and controversial role for adipose tissue mass in breast cancer risk. Factors such as insulin-like growth factors, sex steroids, adipokines and obesity-related inflammatory markers have been postulated as potential effectors of the mechanisms by which obesity and associated metabolic disorders influence breast cancer risk. In this study we evaluated the associations between obesity indices, insulin resistance, circulating adipokines, sex steroids and breast cancer.. Fasting adiponectin, leptin, insulin resistance (homeostasis model assessment, HOMA-IR), testosterone, estradiol, sex hormone binding globulin (SHBG), LH and FSH were determined in 144 newly-diagnosed histologically confirmed breast cancer patients and 77 controls. Univariate and multivariate regression analyses were used to find the associations of these variables with each other, indices of obesity and with breast cancer.. BMI, waist circumference, HOMA-IR and leptin were significantly (P<0.001) higher in patients than in controls. Adiponectin level was also significantly (P<0.05) higher in patients compared to controls. Adiponectin and leptin showed significant correlations with insulin and HOMA-IR but only adiponectin was significantly correlated with estradiol and SHBG. Logistic regression analyses showed that factors associated with breast cancer were BMI [OR (95% CI) =2.8 (1.4-5.5), P=0.004]; high levels of adiponectin [5.1 (2.2-11.5), P<0.001); hyperinsulinaemia [1.1 (1.0-1.1), P=0.01], leptin [3.1 (1.7-5.7), P<0.0001], estradiol [2.5 (1.3-4.7), P=0.005] and testosterone [1.3 (1.03-1.7), P=0.03].. Our findings confirm that adipokines, insulin resistance and sex steroids are associated with breast cancer. The paradoxical association of increased adiponectin with breast cancer is a novel finding that deserves further investigation.

    Topics: Adipokines; Body Mass Index; Breast Neoplasms; Female; Genetic Association Studies; Gonadal Steroid Hormones; Humans; Insulin Resistance; Leptin

2012
[Leptin promotes the expression of hTERT via STAT3 in breast cancer cells].
    Zhonghua yi xue za zhi, 2012, Sep-11, Volume: 92, Issue:34

    To discussion the in vitro molecular mechanism of leptin promoting the expression of hTERT in breast cancer cells.. The hTERT mRNA expression of STAT3 knockdown on leptin-induced hTERT was measured by reverse transcription-polymerase chain reaction (RT-PCR). Determine the expression of hTERT protein after different treatments in MCF7 by Western blot. Chromatin immunoprecipitation assay (ChIP) was performed to detect the binding of STAT3 to hTERT promoter in MCF7. Luciferase assay was used to confirm the effects of leptin and STAT3 phosphorylation inhibitor on the transcriptional activity of hTERT promoter.. The RT-PCR analysis showed that knockdown of STAT3 significantly reduced the leptin-induced transcription of hTERT. Western blot showed that the expression of hTERT were 3.109 ± 0.051 and 1.025 ± 0.031 after leptin or both of leptin and AG490 treatments. The results of CHIP showed that the mRNA of control and leptin (160 ng/ml) treatment were 1 and 3.311 ± 0.017. Leptin increased the combination of STAT3 and hTERT promoter. Luciferase assay showed that when the concentration of leptin was 160 ng/ml, the hTERT promoter activity was 80.98 ± 0.18 while the control was 20.76 ± 0.31. After AG490 treatment, the hTERT promoter activity was 18.65 ± 0.32,significantly reduced the leptin-induced activity of hTERT promoter.. Leptin/STAT3 signaling is a novel pathway for the up-regulation of hTERT expression in breast cancer cells.

    Topics: Breast Neoplasms; Gene Knockdown Techniques; Humans; Leptin; MCF-7 Cells; Signal Transduction; STAT3 Transcription Factor; Telomerase

2012
Evidence of an autocrine role for leptin and leptin receptor in human breast cancer.
    Cancer genomics & proteomics, 2012, Volume: 9, Issue:6

    We studied potential associations between the expression of leptin, leptin receptor (LEPR) and clinicopathological parameters of breast cancer, and the correlation of leptin with human telomerase reverse transcriptase (hTERT) and cyclooxygenase 2 (COX2). A total of 153 specimens were studied. Transcript levels were determined using quantitative polymerase chain reaction (qPCR), and were correlated with clinicopathological data collected for over 10 years. Additionally, leptin and LEPR expression was studied in several breast cell lines.. Both leptin and LEPR mRNA expression were higher in malignant samples (p=0.0011 and 0.0014 respectively). Both were also expressed in MDA436 and MCF7 cell lines. Leptin showed a significant correlation with LEPR (r=0.504, p=0.0000000222). Leptin did not correlate significantly with clinical stage, tumour grade, or with the expression of hTERT or COX2.. This study demonstrates that leptin and LEPR are more readily expressed in cancerous tissues suggesting a possible autocrine role in mammary carcinogenesis, which may be independent of hTERT and COX2 genes.

    Topics: Autocrine Communication; Breast Neoplasms; Cell Line, Tumor; Cyclooxygenase 2; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; MCF-7 Cells; Neoplasm Grading; Neoplasm Staging; Receptors, Leptin; RNA, Messenger; Telomerase

2012
Benzyl isothiocyanate inhibits oncogenic actions of leptin in human breast cancer cells by suppressing activation of signal transducer and activator of transcription 3.
    Carcinogenesis, 2011, Volume: 32, Issue:3

    Molecular effects of obesity, a well-established risk factor for breast cancer progression, are mediated by adipocytokine leptin. Given the important role of leptin in breast cancer growth and metastasis, novel strategies to antagonize biological effects of this adipocytokine are much desired. We showed previously that benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g. garden cress), confers significant protection against mammary carcinogenesis in a transgenic mouse model. The present study provides first evidence for the efficacy of BITC against oncogenic effects of leptin. The BITC treatment circumvented leptin-induced clonogenicity and anchorage-independent growth of MDA-MB-231 and MCF-7 human breast cancer cells. Leptin-stimulated migration and invasion of these cells was also inhibited in the presence of BITC. Analysis of the underlying molecular mechanisms revealed that BITC treatment suppressed leptin-induced Stat3 phosphorylation and cyclin D1 transactivation. The BITC-mediated inhibition of MDA-MB-231 xenograft growth correlated with a modest yet significant decrease in levels of Tyr705 phosphorylated Stat3. The BITC treatment efficiently inhibited Stat3 and SRC1 recruitment to cyclin D1 promoter in a chromatin immunoprecipitation analysis. Furthermore, overexpression of constitutively active Stat3 imparted significant protection against BITC-mediated inhibition of cyclin D1 transactivation, whereas RNA interference of Stat3 resulted in a significant increase in BITC-mediated inhibition of cyclin D1 transactivation in the presence of leptin. These results indicate that Stat3 plays an important role in BITC-mediated inhibition of leptin-induced cyclin D1 transactivation. In conclusion, BITC could potentially be a rational therapeutic strategy for breast carcinoma in obese patients with high leptin levels.

    Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Chromatin Immunoprecipitation; Cyclin D1; Humans; Immunoenzyme Techniques; Isothiocyanates; Leptin; Luciferases; Oncogenes; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Wound Healing

2011
The activation of leptin-mediated survivin is limited by the inducible suppressor SOCS-3 in MCF-7 cells.
    Experimental biology and medicine (Maywood, N.J.), 2011, Volume: 236, Issue:1

    Although leptin has been found to be implicated in obesity-related breast carcinogenesis in postmenopausal women, the molecular mechanisms involved are yet to be defined. Recently, the antiapoptotic gene survivin has been recognized as a target gene for leptin in breast cancer. The aim of this study was to investigate the effect of leptin on the expression of survivin and on the transcriptional activity of its promoter in MCF-7 breast cancer cells. We also studied the potential involvement of SOCS-3 (a negative regulator of leptin's main signaling pathway JAK2/STAT3) in the expression of leptin-mediated survivin. Our results showed a significant increase in the mRNA (dose-dependent increase of 40-70%) and protein expression levels of survivin 24 h post-leptin treatment, which was followed by a significant decrease at 48 and 72 h (of 60-70%). In accordance, a chromatin immunoprecipitation assay revealed an initial strong binding of STAT3 to the survivin promoter, which was no longer detected after 24 h. Myc/mad/max network proteins and histone H3 acetylation status were not found to contribute to the expression of leptin-mediated survivin. Furthermore, a protein immunoprecipitation assay detected an enhanced SOCS-3 binding to the long isoform of leptin's receptor (Ob-Rb) 48 and 72 h after leptin administration, thus conferring inhibition to leptin signaling. In conclusion, our findings suggest, for the first time to our knowledge, that the effect of leptin on the antiapoptotic gene survivin is limited by the inhibitory role of SOCS-3 in the leptin-activated JAK2/STAT3 signaling pathway in MCF-7 breast cancer cells.

    Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Chromatin Immunoprecipitation; Dose-Response Relationship, Drug; Female; Humans; Inhibitor of Apoptosis Proteins; Janus Kinase 2; Leptin; Microtubule-Associated Proteins; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Survivin

2011
Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer.
    European journal of cancer (Oxford, England : 1990), 2011, Volume: 47, Issue:10

    Triple-negative breast cancers, which represent 10-20% of all mammary tumours, are characterised by the aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer development. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed. Here we examined if the leptin (obesity hormone) receptor is a viable target for the treatment of this cancer subtype. In human triple-negative breast cancer tissues, the leptin receptor was expressed in 92% (64/69) and leptin in 86% (59/69) of cases. In a model triple-negative breast cancer cell line MDA-MB-231, the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation at 50 pM concentration. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously significantly extended the average survival time from 15.4 days (untreated controls) to 24 and 28.1 days at 0.1 and 1mg/kg/day doses, respectively. In parallel, conventional treatment with 1mg/kg/day intraperitoneal cisplatin prolonged the average survival time to 18.6 days, while administration of 20mg/kg/day oral Tamoxifen (negative control) had no significant survival effects relative to controls. In normal CD-1 mice, Allo-aca produced no systemic toxicity up to the highest studied subcutaneous bolus dose of 50mg/kg, while, as expected, it induced a modest 6-10% body weight increase. Our results indicate that leptin receptor antagonists could become attractive options for triple-negative breast cancer treatment, especially in the obese patient population.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; In Situ Hybridization, Fluorescence; Infusions, Subcutaneous; Leptin; Mice; Neoplasm Transplantation; Obesity; Peptides; Receptor, ErbB-2; Receptors, Leptin; Tamoxifen; Time Factors; Treatment Outcome

2011
Adipokines, insulin resistance, metabolic syndrome, and breast cancer recurrence: a cohort study.
    Breast cancer research : BCR, 2011, Mar-30, Volume: 13, Issue:2

    Several in vitro studies have suggested the effects of adipokines and insulin resistance on breast cancer cell proliferation and survival. However, little is known about the clinical significance of these findings.. We examined associations between breast cancer recurrence and adiponectin, leptin, insulin resistance, and metabolic syndrome (MetS) in a cohort of 747 patients from 2001 to 2004.. Adjusted hazard ratios showed an inverse trend across the quartiles for serum adiponectin concentration in estrogen receptor (ER)/progesterone receptor (PR) -negative patients (P for trend = 0.027) but not in ER/PR-positive patients. Compared to the highest quartile for adiponectin level, the lowest quartile showed a hazard ratio of 2.82 (1.03 to 7.68). Homeostasis model assessment for insulin resistance (HOMA-IR) showed a positive trend for recurrence in the ER/PR-negative group (P for trend = 0.087) and a negative trend in the ER/PR-positive group (P for trend = 0.081). Leptin did not show any associations (P for trend >0.05). A linear trend was observed with the number of components of MetS in ER/PR-negative patients (P for trend = 0.044). This association disappeared when adjusted for adiponectin and HOMA-IR.. Adiponectin and HOMA-IR have prognostic significance in breast cancer recurrence and interventions related to these factors may protect against recurrence in ER/PR-negative patients. These findings were not observed in the case of ER/PR-positive patients. Further evaluation of these insignificant associations is needed because it might be biased by adjuvant chemotherapy or other confounders.

    Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Cell Proliferation; Cohort Studies; Female; Humans; Insulin Resistance; Leptin; Metabolic Syndrome; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Receptors, Estrogen; Receptors, Progesterone

2011
Common genetic variation in adiponectin, leptin, and leptin receptor and association with breast cancer subtypes.
    Breast cancer research and treatment, 2011, Volume: 129, Issue:2

    Adipocytokines are produced by visceral fat, and levels may be associated with breast cancer risk. We investigated whether single nucleotide polymorphisms (SNPs) in adipocytokine genes adiponectin (ADIPOQ), leptin (LEP), and the leptin receptor (LEPR) were associated with basal-like or luminal A breast cancer subtypes. 104 candidate and tag SNPs were genotyped in 1776 of 2022 controls and 1972 (200 basal-like, 679 luminal A) of 2311 cases from the Carolina Breast Cancer Study (CBCS), a population-based case-control study of whites and African Americans. Breast cancer molecular subtypes were determined by immunohistochemistry. Genotype odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Haplotype ORs and 95% CIs were estimated using Hapstat. Interactions with waist-hip ratio were evaluated using a multiplicative interaction term. Ancestry was estimated from 144 ancestry informative markers (AIMs), and included in models to control for population stratification. Candidate SNPs LEPR K109R (rs1137100) and LEPR Q223R (rs1137101) were positively associated with luminal A breast cancer, whereas ADIPOQ +45 T/G (rs2241766), ADIPOQ +276 G/T (rs1501299), and LEPR K656N (rs8129183) were not associated with either subtype. Few patterns were observed among tag SNPs, with the exception of 3 LEPR SNPs (rs17412175, rs9436746, and rs9436748) that were in moderate LD and inversely associated with basal-like breast cancer. However, no SNP associations were statistically significant after adjustment for multiple comparisons. Haplotypes in LEP and LEPR were associated with both basal-like and luminal A subtypes. There was no evidence of interaction with waist-hip ratio. Data suggest associations between LEPR candidate SNPs and luminal A breast cancer in the CBCS and LEPR intron 2 tag SNPs and basal-like breast cancer. Replication in additional studies where breast cancer subtypes have been defined is necessary to confirm these potential associations.

    Topics: Adiponectin; Adult; Aged; Breast Neoplasms; Case-Control Studies; Chi-Square Distribution; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Immunohistochemistry; Leptin; Logistic Models; Middle Aged; Monte Carlo Method; North Carolina; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Receptors, Leptin; Risk Assessment; Risk Factors; Waist-Hip Ratio; Young Adult

2011
Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells.
    Endocrine-related cancer, 2011, Volume: 18, Issue:4

    Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation of Notch1 and the release of a transcriptionally active Notch1 intracellular domain (NICD). Chromatin immunoprecipitation analysis shows that NICD gets recruited to the survivin promoter at the CSL (CBF1/RBP-Jk, Su(H), Lag-1) binding site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of epidermal growth factor receptor (EGFR) is involved in leptin-mediated Notch1 and survivin upregulation, demonstrating a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors, such as lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic strategy. This conclusion is supported by in vivo data showing the overexpression of leptin and survivin in epithelial cells of high-grade ductal carcinomas in situ and in high-grade invasive carcinomas.

    Topics: Animals; Blotting, Western; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Chromatin Immunoprecipitation; ErbB Receptors; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Immunoprecipitation; Inhibitor of Apoptosis Proteins; Leptin; Mice; Mice, Nude; Receptor, Notch1; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Survivin; Up-Regulation; Wound Healing

2011
Influence of the metabolic syndrome on leptin and leptin receptor in breast cancer.
    Molecular carcinogenesis, 2011, Volume: 50, Issue:8

    Obesity and its associated metabolic syndrome (MetS) are recognized risk factors for breast cancer. The molecular basis for this association remains largely unknown. Adipokines, in particular leptin and adiponectin, are thought to form part of the mechanism linking obesity with cancer through their altered expression/production either systemically (endocrine pathway) or locally (paracrine/autocrine pathway). Using quantitative PCR, mRNA expression of adiponectin (AdipoQ) and leptin (Ob) in mammary adipose tissue (MAT), intratumoral leptin and associated ligand receptors (ObR, AdipoR1, and AdipoR2) was examined in 77 patients with complete anthropomorphic and serological data. Expression of Ob in MAT, and ObR in matched tumor tissue was significantly higher in patients with MetS compared to obese only or normal weight cancer patients (P < 0.005). There was no difference in intratumoral leptin adiponectin or its ligand receptors in the same groups. Individual features of MetS correlated with Ob and ObR expression, but not obesity markers (BMI, waist circumference). mRNA expression of leptin (Ob) and ObR, in adipose tissue and matched tumor samples, respectively, appear to be associated with obesity status in breast cancer. Increasing insulin resistance is a predominant feature of this higher Ob/ObR expression observed. These novel data indicate that the MetS may be an amenable risk factor for breast cancer.

    Topics: Adiponectin; Adipose Tissue; Adult; Aged; Aged, 80 and over; Breast; Breast Neoplasms; Cohort Studies; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Metabolic Syndrome; Middle Aged; Receptors, Adiponectin; Receptors, Leptin; RNA, Messenger

2011
Proteomic analysis of MCF-7 breast cancer cell line exposed to leptin.
    Analytical cellular pathology (Amsterdam), 2011, Volume: 34, Issue:3

    Obesity is a well-known factor risk for breast cancer in postmenopausal women. Circulating leptin levels are increased in obese and it has been suggested to play an important role in mammary tumor formation and progression. To contribute to the understanding of the molecular mechanisms underlying leptin action in breast cancer, our aim was to identify proteins regulated by leptin in MCF-7 human breast cancer cells.. We used two-dimensional gel electrophoresis (2-DE) and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) to identify proteins affected by leptin.. Thirty proteins were found differentially expressed in MCF-7 cells after 48 h leptin exposure. Proteins regulated by leptin included proteins previously implicated in breast cancer such as catechol-o-methyltransferase, cathepsin D, hsp27, serine/threonine-protein phosphatase and regulatory proteins of the Ras signaling pathway. Proteins involved in other cellular functions such as stress response, cytosqueleton remodeling and proteins belonging to ubiquitin-proteasome system, were also identified. Furthermore, leptin-treated cells showed a substantial uptake of the serum carrier proteins albumin and alpha-2-HS-glycoprotein.. This screening reveals that leptin influences the levels of key proteins involved in breast cancer which opens new avenues for the study of the molecular mechanisms linking obesity to breast cancer.

    Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Electrophoresis, Gel, Two-Dimensional; Female; Humans; Leptin; Neoplasm Proteins; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Time Factors

2011
Plasma leptin levels and risk of breast cancer in premenopausal women.
    Cancer prevention research (Philadelphia, Pa.), 2011, Volume: 4, Issue:9

    Body mass index (BMI) is inversely related to the risk of premenopausal breast cancer, but the underlying biological mechanisms of this association are poorly understood. Leptin, a peptide hormone produced primarily by adipocytes, is a potential mediator of the BMI association because BMI and total body fat are positively associated with circulating leptin levels and leptin and its receptor are overexpressed in breast tumors. We conducted a prospective case-control study nested within the Nurses' Health Study II cohort examining the association between plasma leptin levels in premenopausal women and breast cancer risk. Leptin was measured in blood samples collected between 1996 and 1999. The analysis included 330 incident breast cancer cases diagnosed after blood collection and 636 matched controls. Logistic regression models, controlling for breast cancer risk factors, were used to calculate ORs and 95% CIs. After adjustment for BMI at age 18, weight change since age 18 to blood draw, and other breast cancer risk factors, plasma leptin levels were inversely associated with breast cancer risk (OR for top vs. bottom quartile = 0.55; 95% CI = 0.31-0.99; P(trend) = 0.04). Adjustment for BMI at blood draw attenuated the association (OR = 0.69; 95% CI = 0.38-1.23; P(trend) = 0.26). Our results suggest that leptin may be inversely associated with breast cancer risk, but it is unclear whether any part of this association is independent of BMI.

    Topics: Adult; Body Mass Index; Breast Neoplasms; Case-Control Studies; Cohort Studies; Female; Humans; Leptin; Middle Aged; Premenopause; Prospective Studies; Receptors, Leptin; Regression Analysis; Risk; Risk Factors

2011
Associations of single nucleotide polymorphisms in the adiponectin gene with adiponectin levels and cardio-metabolic risk factors in patients with cancer.
    Disease markers, 2011, Volume: 30, Issue:4

    The aims of this study are to (1) study the influence of polymorphisms in adiponectin gene on adiponectin levels and potential associations with breast, prostate and colon cancer; (2) investigate the associations of adiponectin levels with other adipokines and breast, prostate and colon cancers.. We measured fasting adiponectin, leptin, insulin, Sex steroids in 132 (66 females, 66 males) cancer patients and 68 age and sex matched apparently healthy subjects. Body Mass Index (BMI) and waist circumference were used as indices of obesity. Insulin Resistance was assessed using Homeostasis Model Assessment (HOMA). Three single nucleotide polymorphisms (SNP rs182052 (G-10066-A), SNP rs1501299 (276G > T), SNP rs224176 (45T > G) in adiponectin gene were studied using Real Time Polymerase Chain Reaction.. GG genotype of SNP rs1501299 was significantly associated with higher levels of adiponectin (OR=1.2, 95%CI(1.03-1.3), p = 0.02); breast (OR=8.6, 95%CI(1.03-71), p = 0.04), colon cancers (OR= 12, 95%CI(1.2-115), p =0.03). GT genotype was also associated significantly with colon cancer (OR=2.6, 95%CI (1.1-6), p =0.03). However SNP rs224176 was associated with only breast cancer.. Our results demonstrate that adiponectin gene SNP rs1501299 and SNP rs224176 may be the predisposing factors in some cancers but our results differ from what has been reported in other populations suggesting a complex relationship between genetic variations and phenotypic adiponectin levels.

    Topics: Adiponectin; Adult; Aged; Body Mass Index; Breast Neoplasms; Case-Control Studies; Colonic Neoplasms; Female; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Risk Factors; Waist Circumference

2011
In vivo and in vitro evidence that PPARγ ligands are antagonists of leptin signaling in breast cancer.
    The American journal of pathology, 2011, Volume: 179, Issue:2

    Obesity is a major risk factor for the development and progression of breast cancer. Leptin, a cytokine mainly produced by adipocytes, plays a crucial role in mammary carcinogenesis and is elevated in hyperinsulinemia and insulin resistance. The antidiabetic thiazolidinediones inhibit leptin gene expression through ligand activation of the peroxisome proliferator-activated receptor-γ (PPARγ) and exert antiproliferative and apoptotic effects on breast carcinoma. In this study, we investigated the ability of PPARγ ligands to counteract leptin stimulatory effects on breast cancer growth in either in vivo or in vitro models. The results show that activation of PPARγ prevented the development of leptin-induced MCF-7 tumor xenografts and inhibited the increased cell-cell aggregation and proliferation observed on leptin exposure. PPARγ ligands abrogated the leptin-induced up-regulation of leptin gene expression and its receptors in breast cancer. PPARγ-mediated repression of leptin gene involved the recruitment of nuclear receptor corepressor protein and silencing mediator of retinoid and thyroid hormone receptors corepressors on the glucocorticoid responsive element site in the leptin gene expression regulatory region in the presence of glucocorticoid receptor and PPARγ. In addition, PPARγ ligands inhibited leptin signaling mediated by MAPK/STAT3/Akt phosphorylation and counteracted leptin stimulatory effect on estrogen signaling. These findings suggest that PPARγ ligands may have potential therapeutic benefits in the treatment of breast cancer.

    Topics: Animals; Breast Neoplasms; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Female; Humans; In Vitro Techniques; Leptin; Ligands; Mammary Neoplasms, Animal; Mice; Mice, Nude; Obesity; PPAR gamma; Receptors, Glucocorticoid; Receptors, Thyroid Hormone; Risk Factors; RNA Interference; Signal Transduction

2011
Elevated serum visfatin/nicotinamide phosphoribosyl-transferase levels are associated with risk of postmenopausal breast cancer independently from adiponectin, leptin, and anthropometric and metabolic parameters.
    Menopause (New York, N.Y.), 2011, Volume: 18, Issue:11

    Obesity has been implicated in the etiology of postmenopausal breast cancer (PBC). We hypothesized that altered secretion of visfatin may underlie this association. We thus investigated the association of serum visfatin with PBC risk, taking into account known risk factors including adipokines and anthropometric and metabolic parameters.. In a case-control study, we studied 102 postmenopausal women with pathologically confirmed, incident invasive breast cancer and 102 control women matched on age and time of diagnosis between 2003 and 2010 at Army Share Fund Hospital, Veterans' Hospital (NIMTS). Levels of serum visfatin, adiponectin, leptin, metabolic parameters, carcinoembryonic antigen, and CA 15-3 were determined.. The mean serum visfatin level was significantly higher in case than in control participants (P < 0.001). Women in the highest quartile of visfatin concentration presented significantly higher odds for PBC, adjusting for age, date of diagnosis, education, body mass index, waist circumference, years with menstruation, parity/age at first full-term pregnancy, breast-feeding, family history of cancer, use of exogenous hormones, alcohol consumption, smoking status, homeostasis model assessment score, and serum leptin and adiponectin concentrations (odds ratio, 7.93; 95% CI, 2.52-24.9). In case participants, the visfatin level correlated significantly with the tumor marker CA 15-3 (P = 0.03) but not with metabolic and anthropometric variables (P > 0.05).. Further prospective studies are needed to determine whether an elevated serum visfatin level is implicated in the etiopathogenesis of PBC or reflects changes during PBC progression and could therefore be used as a biomarker for PBC.

    Topics: Adiponectin; Aged; Aged, 80 and over; Biomarkers; Breast Neoplasms; Carcinoembryonic Antigen; Case-Control Studies; Cytokines; Female; Humans; Leptin; Logistic Models; Middle Aged; Mucin-1; Nicotinamide Phosphoribosyltransferase; Obesity; Odds Ratio; Postmenopause; Risk

2011
The antiproliferative effects of pterostilbene on breast cancer in vitro are via inhibition of constitutive and leptin-induced Janus kinase/signal transducer and activator of transcription activation.
    American journal of surgery, 2011, Volume: 202, Issue:5

    The hormone leptin is implicated in breast carcinogenesis in obese women. One mechanism is through its activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT3) and apoptosis dysregulation. We have shown that the antioxidant pterostilbene inhibits proliferation and induces apoptosis in breast cancer. Therefore, the goal of this study was to evaluate the effect of pterostilbene on cell proliferation and JAK/STAT3 signaling in leptin-stimulated breast cancer.. Breast cancer cells were treated with leptin alone or in combination with pterostilbene. Detection of cell proliferation and JAK/STAT3 signaling were performed using enzyme-linked immunosorbent assay protocols. Statistical analysis was performed with analysis of variance and Tukey post hoc analysis.. Pterostilbene suppresses constitutive as well as leptin-induced JAK/STAT3 activation. Pterostilbene treatment also inhibited leptin-induced cell proliferation.. Pterostilbene has an inhibitory effect on leptin-stimulated breast cancer in vitro through reduction of cell proliferation and JAK/STAT3 signaling, a critical regulatory component of tumorigenesis in obesity-related breast cancer.

    Topics: Antioxidants; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Humans; Janus Kinases; Leptin; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Transcriptional Activation

2011
Chronic leptin treatment sensitizes MCF-7 breast cancer cells to estrogen.
    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2011, Volume: 28, Issue:5

    Obesity is associated with an increased risk of estrogen-dependent breast cancer. The adipokine leptin, whose levels are chronically increased in obese people, has been shown to stimulate ER positive cancer cell growth. Considering previous evidence of a crosstalk between leptin and estrogen signaling, the objective of this study was to establish the influence of chronic leptin treatment on estrogen-dependent cell growth.. To this aim, we use the estrogen receptor (ER) positive MCF-7 breast cancer cell line treated chronically with leptin and analyzed estrogen-dependent cell growth, ERs (ERα and ERβ) expression, ER-dependent transcriptional activity as well as cell survival to the antiestrogenic agents tamoxifen and ICI 182,780.. Leptin signaling pathway kept activated after chronic stimulation (7 days) with leptin showing significant phosphorylation of JAK2 and STAT3 and higher cell proliferation rate. Chronic leptin at 100 ng/mL dose increased ERα to ERβ ratio and consistently enhanced estrogen-dependent transcriptional activity, increasing E2-dependent cell growth and resistance to antiestrogen agents.. This study supports the existence of a crosstalk between leptin and estrogen, in which leptin might play an important role potentiating the mitogenic action of estrogen, probably by alteration of ERα to ERβ ratio.

    Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens; Female; Fulvestrant; Humans; Janus Kinase 2; Leptin; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tamoxifen

2011
Preoperative serum leptin levels in patients with breast cancer.
    Medical oncology (Northwood, London, England), 2010, Volume: 27, Issue:2

    Leptin is an adipocyte-derived protein and plays an important role in the control of body weight by acting as a neurohormone regulating energy balance and food intake in the hypothalamus. The high serum leptin levels and the overexpression of leptin receptors have been documented in breast cancer patients, but the levels never checked preoperatively. In the present study, the relationship between preoperative serum leptin levels of the breast cancer patients and the healthy controls were evaluated. The serum leptin levels in 30 breast cancer patients were compared to 30 healthy female volunteers. In addition, the association of serum leptin levels and the various well-known risk factors were studied. Serum leptin levels of patients with breast cancer (28.55 + 19.7 ng/ml) were tended to be higher than those of controls (26.43 + 19.4 ng/ml), but it did not reach statistical difference (P = 0.712). There was significant correlation between the expression of ER, PR, and serum leptin levels (P = 0.018 and 0.037, respectively), but not with the HER-2/neu receptor expression (P = 0.067). Also association was not found between the tumor size, lymph node involvement, and the levels of serum leptin (P = 0.235, 0.34, and 0.86, respectively). The serum leptin level was also found to be similar in premenopausal (24.85 +/- 18.14 ng/ml) and postmenopausal (30.49 +/- 17.19 ng/ml) patients (P = 0.235). The preoperative serum leptin levels in breast cancer patients were similar to healthy controls. In subset analysis, the significant correlation between the leptin level and hormonal status was noted, but association with HER-2/neu was not detected. These findings should be confirmed with larger studies.

    Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Middle Aged; Postmenopause; Premenopause; Preoperative Care; Risk Factors; Young Adult

2010
Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival.
    Breast cancer research and treatment, 2010, Volume: 120, Issue:3

    Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. A modest increase in risk of developing breast cancer was associated with the LEP -2548AA genotype when compared to the LEP -2548GG genotype (age-adjusted OR = 1.30; 95% CI = 1.01-1.66). This association was stronger among postmenopausal women who were obese (OR = 1.86; 95% CI = 0.95-3.64) although the interaction was of borderline statistical significance (P = 0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time = 66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis.

    Topics: Breast Neoplasms; Case-Control Studies; Cause of Death; Europe; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genotype; Humans; Incidence; Leptin; Menopause; New York; Obesity; Polymorphism, Single Nucleotide; Proportional Hazards Models; Receptors, Leptin; Risk Factors; Survival Analysis

2010
Oxidant/antioxidant status, lipids and hormonal profile in overweight women with breast cancer.
    Pathology oncology research : POR, 2010, Volume: 16, Issue:2

    This study was carried out to determine the relationships between leptin concentrations, lipid alterations, oxidant/ antioxidant status, in vitro LDL oxidizability and LDL-fatty acid composition in overweight breast cancer patients. Glucose, insulin, leptin, lipids, LDL-cholesteryl ester fatty acids, markers of oxidant status (MDA, Hydroperoxides, carbonyl proteins, conjugated dienes) and markers of antioxidant status (vitamins A, C, E, erythrocyte activities of the enzymes superoxide dismutase, SOD, catalase, glutathione peroxidase,GPx, and glutathione reductase, GR and the serum total antioxidant status, ORAC) were investigated in breast cancer patients and in control women. Our findings showed that insulin, leptin, triglyceride, cholesterol and LDL-C concentrations were increased in patients compared to controls. ORAC and vitamin C and E values were lower while plasma hydroperoxide, carbonyl protein and conjugated diene levels, SOD and GPx activities were higher than in controls. Alterations in LDL-fatty acid composition were associated with their enhanced oxidative susceptibility. There were significant positive correlations between leptin concentrations and LDL-C, hydroperoxides, carbonyl proteins, SOD activity, baseline conjugated diene levels and oxidation rate, and significant negative correlations between leptin and ORAC, lag time and LDL-PUFA in patients. In conclusion, breast cancer is associated with lipid alterations and enhanced oxidative stress linked to high leptin levels in overweight.

    Topics: Adult; Antioxidants; Ascorbic Acid; Body Mass Index; Breast Neoplasms; Catalase; Female; Glutathione Peroxidase; Glutathione Reductase; Humans; Leptin; Lipoproteins; Middle Aged; Neoplasm Staging; Overweight; Oxidative Stress; Superoxide Dismutase; Vitamin A; Vitamin E

2010
Adipocyte fatty acid-binding protein as a novel prognostic factor in obese breast cancer patients.
    Breast cancer research and treatment, 2010, Volume: 119, Issue:2

    Several adipocytokines, such as leptin or adiponectin, are associated with obesity and the risk for breast cancer. Adiopcyte fatty acid binding-protein(A-FABP) is another protein found in adipose tissue;therefore, we investigated the association of A-FABP with the occurrence and prognosis of breast cancer. In our study,200 women attending the University of Ulm for breast surgery between the years 2005 and 2007 were included;159 had histologically confirmed breast cancer; 41 had histologically confirmed benign lesions. Serum levels ofA-FABP, leptin, and adiponectin were measured, and their relationship to body-mass-index (BMI), breast cancer, and tumor characteristics were analyzed; logistic regression model was adjusted to age, BMI, menopausal status, use of Hormone Replacement Therapy (HRT), and family history of breast cancer. Serum A-FABP levels were found to be significantly higher in obese (BMI C 25) than in non-obese women (BMI B 24.9), 41.16 ng/ml and 24.95 ng/ml,respectively (P\\0.0001). Independent of obesity, the serum A-FABP levels were significantly higher in breast cancer patients (34.65 ng/ml) than in healthy controls(24.47 ng/ml), P\\0.0001; the odds ratio (1.038, P\\0.05,95% confidence interval 1.001-1.72) showed a significant association of A-FABP with breast cancer risk. Serum leptin levels showed a strong correlation with BMI(rs = 0.78) and were significantly higher in breast cancer patients (20.87 ng/ml) than in controls (14.90 ng/ml),P\\0.05. In contrast, adiponectin showed no significant association with breast cancer. Concerning tumor characteristics,A-FABP was positively connected with tumor size (T C 2 cm, P\\0.05) and nodal-status (P\\0.05).Our study reveals that high A-FABP serum levels are associated with obesity, breast cancer risk, and adverse tumor characteristics.

    Topics: Adiponectin; Adult; Aged; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Case-Control Studies; Fatty Acid-Binding Proteins; Female; Humans; Leptin; Logistic Models; Middle Aged; Neoplasm Staging; Obesity; Odds Ratio; Postmenopause; Predictive Value of Tests; Premenopause; Risk Assessment; Risk Factors; Treatment Outcome; Up-Regulation

2010
Expression of estrogen receptor alpha increases leptin-induced STAT3 activity in breast cancer cells.
    International journal of cancer, 2010, Jul-01, Volume: 127, Issue:1

    Adipositas correlates with an enhanced risk of developing malignant diseases such as breast cancer, endometrial tumor or prostate carcinoma, but the molecular basis for this is not well understood. Potential mechanisms include increased bioavailability of adipocytokines (e.g. leptin) and steroid hormones. Here, we investigated cross-talk between ERalpha (estrogen receptor alpha) and leptin-induced activation of signal transducer and activator of transcription 3 (STAT3), a transactivator of important oncogenes. Upon leptin binding to its receptor Ob-RL (obesity receptor), STAT3 tyrosine phosphorylation and transactivation activity were enhanced by simultaneously expressing ERalpha. Downregulation of ERalpha using small interfering RNA abolished leptin-induced STAT3 phosphorylation. Interestingly, leptin-mediated STAT3 activation was unaffected by co-stimulation with the ERalpha ligands estradiol (E2) or estrogen antagonists ICI182,780 and tamoxifen, implying that enhancement of leptin-mediated STAT3 activity is independent of ERalpha ligands. We also detected ERalpha binding to STAT3 and JAK2 (Janus kinase 2), resulting in enhanced JAK2 activity upstream of STAT3 in response to leptin that might lead to an increased ERalpha-dependent cell viability. Altogether, our results indicate that leptin-induced STAT3 activation acts as a key event in ERalpha-dependent development of malignant diseases.

    Topics: Base Sequence; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; DNA Primers; Estrogen Receptor alpha; Female; Humans; Leptin; Polymerase Chain Reaction; STAT3 Transcription Factor; Transfection

2010
The relation of leptin and adiponectin with breast density among premenopausal women.
    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 2010, Volume: 19, Issue:1

    The adipocytokine leptin may increase breast cancer risk, while adiponectin may be protective. We examined the association of the two circulating markers with mammographic density, a strong predictor of breast cancer risk. For 183 premenopausal participants of a nutritional trial, mammograms performed at baseline, year 1 and year 2 were assessed for density using a computer-assisted method. Serum samples obtained at the same time were analyzed for leptin and adiponectin by enzyme-linked immunosorbent assay. We applied mixed models to incorporate the repeated measurements while adjusting for confounders including body mass index (BMI). At baseline, the mean age of the participants was 42.6+/-2.9 years; 40% were of Asian ancestry. Leptin was lower and adiponectin higher in normal weight than overweight women. Neither marker was related to absolute breast density. The significant inverse association of leptin with percent density disappeared when BMI was added to the model. After stratification by weight, percent density decreased with higher leptin levels in normal weight women, whereas it increased among overweight participants. After adjustment for BMI, the positive association between percent density and adiponectin was greatly reduced and no longer significant. These results do not support a strong association of leptin or adiponectin with breast cancer risk as assessed by mammographic density. In contrast, the findings suggest the possibility that the inverse association of BMI with breast cancer risk in premenopausal women is mediated by adipocytokines.

    Topics: Adiponectin; Adult; Body Composition; Body Mass Index; Breast; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Mammography; Middle Aged; Premenopause; Randomized Controlled Trials as Topic; Risk Factors

2010
Leptin upregulates telomerase activity and transcription of human telomerase reverse transcriptase in MCF-7 breast cancer cells.
    Biochemical and biophysical research communications, 2010, Mar-26, Volume: 394, Issue:1

    The aim was to analyze the mechanism of leptin-induced activity of telomerase in MCF-7 breast cancer cells. We found that leptin activated telomerase in a dose-dependent manner; leptin upregulated the expression of Human Telomerase Reverse Transcriptase (hTERT) at mRNA and protein levels; blockade of signal transducer and activator of transcription 3 (STAT3) phosphorylation significantly counteracted leptin-induced hTERT transcription and protein expression; chromatin immunoprecipitation analysis showed that leptin enhanced the binding of STAT3 to the hTERT promoter. This study uncovers a new mechanism of the proliferative effect of leptin on breast cancer cells and provides a new explanation of obesity-related breast cancer.

    Topics: Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Male; Obesity; STAT3 Transcription Factor; Telomerase; Transcription, Genetic

2010
Regulation of estrogen receptors alpha and beta in human breast carcinoma by exogenous leptin in nude mouse xenograft model.
    Chinese medical journal, 2010, Feb-05, Volume: 123, Issue:3

    It is essential to clarify the interactions of hormones during the progression of human breast cancer. This study examined the effects of exogenous human leptin on estrogen receptor (ER) alpha and beta in human breast tumor tissue in a nude mouse xenograft model.. We created nude mice xenografts of MCF-7 human breast cancer cells, and randomly divided them into an experimental group and a control group. The mice in experimental group were injected subcutaneously around tumors with human leptin, while the control group were injected with the same dose of normal saline. A real-time RT-PCR assay was developed to quantify the mRNA of ERalpha, beta in the tumor tissues. Western blotting analyses were used to assess the relative quantities of the ERalpha, beta proteins.. Leptin-treated xenografted nude mice were successfully established. The amount of ERalpha mRNA was significantly higher in the leptin group than in the control group (P < 0.01), while the amount of ERbeta mRNA was significantly lower in the leptin group than in the control group (P < 0.01). Western blotting analyses revealed that the ERalpha protein level was significantly higher in the leptin group than in the control group (P < 0.01), while the ERbeta protein level was significantly lower in the leptin group than in the control group (P < 0.01).. Nude mouse xenograft model can be safely and serviceably treated with human leptin by subcutaneous injections around tumor. ERalpha, beta were both targets of leptin in breast cancer. Leptin can up-regulate the expression of ERalpha and down-regulate the expression of the ERbeta in human breast tumor.

    Topics: Animals; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mice; Mice, Nude; Polymerase Chain Reaction; Random Allocation; RNA, Messenger; Xenograft Model Antitumor Assays

2010
Correlation of body mass index and leptin with tumor size and stage of disease in hormone-dependent postmenopausal breast cancer: preliminary results and therapeutic implications.
    Journal of molecular medicine (Berlin, Germany), 2010, Volume: 88, Issue:7

    Obesity is considered the most important risk and prognostic factor for estrogen-dependent breast cancer in postmenopausal women. Adipokines, in particular leptin, are at the center of the etiopathogenetic mechanisms by which obesity and related metabolic disorders influence breast cancer risk and its prognosis. The present prospective observational study aims to investigate the relationship between body mass index (BMI), serum levels of leptin and proinflammatory cytokines, and breast cancer prognostic factors. In the study, 98 postmenopausal and 82 premenopausal patients with ER-positive breast cancer participated. During the same study period, 221 control subjects were simultaneously recruited. Women underwent baseline measurements pre-operatively, before any surgical and systemic treatments. Pathologic characteristics of tumors were abstracted from pathology reports. Leptin and proinflammatory cytokines were assayed in stored fasting blood specimens. In postmenopausal breast cancer patients, BMI, leptin, and interleukin-6 significantly correlated with pathological tumor classification (pT) and TNM stage. Multivariate regression analysis showed that BMI and leptin, but not interleukin-6, were independent predictive variables of pT and TNM stage. Our results seem to suggest a twofold role of leptin in the etiopathogenesis of postmenopausal estrogen-positive breast cancer. Indeed, leptin reflects the total amount of fat mass, which correlates to aromatase activity and subsequent estrogens levels. Further studies are warranted to clarify the role of leptin and interleukin-6 in breast carcinogenesis and identify new therapeutic options, beyond the use of aromatase inhibitors, acting selectively on adipokine-driven pathways.

    Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Breast Neoplasms; Female; Humans; Interleukin-6; Leptin; Middle Aged; Postmenopause; Premenopause; Prognosis; Prospective Studies; Tumor Necrosis Factor-alpha; Young Adult

2010
Cellular and molecular crosstalk between leptin receptor and estrogen receptor-{alpha} in breast cancer: molecular basis for a novel therapeutic setting.
    Endocrine-related cancer, 2010, Volume: 17, Issue:2

    Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-alpha (ERalpha). To this aim, we utilized two human breast cancer cell lines, one ERalpha-positive cell line (MCF 7) and the other ERalpha-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERalpha receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR gene-silencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERalpha, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERalpha. In conclusion, this study suggests a crosstalk between LepR and ERalpha, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

    Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Death; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leptin; Middle Aged; Mitogen-Activated Protein Kinase 3; Neoplasm Staging; Phosphorylation; Receptors, Leptin; Signal Transduction; STAT Transcription Factors; Statistics, Nonparametric

2010
Relationships between hypoxia markers and the leptin system, estrogen receptors in human primary and metastatic breast cancer: effects of preoperative chemotherapy.
    BMC cancer, 2010, Jun-22, Volume: 10

    Tumor hypoxia is marked by enhanced expression of hypoxia-inducible factor-alpha (HIF-1alpha) and glucose transporter-1 (Glut-1). Hypoxic conditions have also been associated with overexpression of angiogenic factors, such as leptin. The aim of our study was to analyze the relationships between hypoxia markers HIF-1alpha, Glut-1, leptin, leptin receptor (ObR) and other breast cancer biomarkers in primary and metastatic breast cancer in patients treated or untreated with preoperative chemotherapy.. The expression of different biomarkers was examined by immunohistochemistry in 116 primary breast cancers and 65 lymph node metastases. Forty five of these samples were obtained form patients who received preoperative chemotherapy and 71 from untreated patients.. In primary tumors without preoperative chemotherapy, HIF-1alpha and Glut-1 were positively correlated (p = 0.02, r = 0.437). HIF-1alpha in primary and metastatic tumors without preoperative therapy positively correlated with leptin (p < 0.0001, r = 0.532; p = 0.013, r = 0.533, respectively) and ObR (p = 0.002, r = 0.319; p = 0.083, r = 0.387, respectively). Hypoxia markers HIF-1alpha and Glut-1 were negatively associated with estrogen receptor alpha (ERalpha) and positively correlated with estrogen receptor beta (ERbeta). In this group of tumors, a positive correlation between Glut-1 and proliferation marker Ki-67 (p = 0.017, r = 0.433) was noted. The associations between HIF-1alpha and Glut-1, HIF-1alpha and leptin, HIF-1alpha and ERalpha as well as Glut-1 and ERbeta were lost following preoperative chemotherapy.. Intratumoral hypoxia in breast cancer is marked by coordinated expression of such markers as HIF-1alpha, Glut-1, leptin and ObR. The relationships among these proteins can be altered by preoperative chemotherapy.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cell Hypoxia; Chemotherapy, Adjuvant; Female; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Ki-67 Antigen; Leptin; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Receptors, Estrogen; Receptors, Leptin; Treatment Outcome

2010
Leptin potentiates antiproliferative action of cAMP elevation via protein kinase A down-regulation in breast cancer cells.
    Journal of cellular physiology, 2010, Volume: 225, Issue:3

    Previously, we have shown that leptin potentiates the antiproliferative action of cAMP elevating agents in breast cancer cells and that the protein kinase A (PKA) inhibitor KT-5720 prevented the antiproliferative effects induced by the leptin plus cAMP elevation. The present experiments were designed to gain a better understanding about the PKA role in the antitumor interaction between leptin and cAMP elevating agents and on the underlying signaling pathways. Here we show that exposure of MDA-MB-231 breast cancer cells to leptin resulted in a strong phosphorylation of both ERK1/2 and STAT3. Interestingly, intracellular cAMP elevation upon forskolin pretreatment completely abrogated both ERK1/2 and STAT3 phosphorylation in response to leptin and was accompanied by a consistent CREB phosphorylation. Notably, leptin plus forskolin cotreatments resulted in a strong decrease of both PKA regulatory RIα and catalytic subunits protein levels. Importantly, pretreatment with the PKA inhibitor KT-5720 blocked the forskolin-induced CREB phosphorylation and prevented both the inhibition by forskolin of leptin-induced ERK1/2 and STAT3 phosphorylation and the PKA subunits down-regulation induced by the combination of leptin and forskolin. Altogether, our results indicate that leptin-dependent signaling pathways are influenced by cAMP elevation and identify PKA as relevantly involved in the pharmacological antitumor interaction between leptin and cAMP elevating drugs in MDA-MB-231 cells. We propose a molecular model by which PKA confers its effects. Potential therapeutic applications by our data will be discussed.

    Topics: Antineoplastic Agents; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Cell Proliferation; Colforsin; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic AMP-Dependent Protein Kinases; Down-Regulation; Enzyme Activators; Female; Humans; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Kinase Inhibitors; Pyrroles; Recombinant Proteins; Signal Transduction; STAT3 Transcription Factor; Time Factors; Up-Regulation

2010
Zinc-alpha2-glycoprotein: a new biomarker of breast cancer?
    Anticancer research, 2010, Volume: 30, Issue:7

    Obesity increases the risk of breast cancer. It is established that adipocyte secretions, i.e. adipokines, may play a role in mammary carcinogenesis. We have shown that two major adipokines, leptin and adiponectin, were expressed in mammary adenocarcinoma.. Here, we evaluated zinc-alpha2-glycoprotein (ZAG) expression in tumor (n=55) and healthy (n=6) breast tissue by immunohistochemistry and examined whether it was correlated with that of major adipokines, usual tumor biomarkers (sex steroids receptors, i.e. estrogen (ER) and progesterone; Ki-67; cErb2), or apoptosis markers (Bcl2 and Bax).. ZAG expression was detected in ductal carcinoma and normal epithelial adjacent tissue but not in normal tissue of healthy women. In cancer tissue, its expression was correlated positively to leptin receptor and negatively to adiponectin receptor and ER.. These preliminary results suggest both a relationship between ZAG expression and pathways involving adipokines or estrogen and that ZAG may be a potential breast cancer biomarker.

    Topics: Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Apoptosis; bcl-2-Associated X Protein; Biomarkers, Tumor; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Carrier Proteins; Case-Control Studies; Female; Glycoproteins; Humans; Immunohistochemistry; Leptin; Middle Aged; Proto-Oncogene Proteins c-bcl-2

2010
Postdiagnosis diet quality is inversely related to a biomarker of inflammation among breast cancer survivors.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2010, Volume: 19, Issue:9

    Inflammation and immune response have potential prognostic implications for breast cancer survivors. We examined how postdiagnosis diet quality is cross-sectionally related to biomarkers of inflammation and adipose-derived hormones among breast cancer survivors and determined whether physical activity or body size modified any observed associations.. Participants included 746 women diagnosed with stage 0 to IIIA breast cancer. Thirty months after diagnosis, the women completed food frequency questionnaires. We scored diet quality with the Healthy Eating Index (HEI)-2005. Serum concentrations of C-reactive protein (CRP), serum amyloid A, leptin, and adiponectin were measured in fasting 30 mL blood samples. Log biomarker values were regressed on quartiles of HEI-2005 scores in multivariate models, and beta scores were exponentiated and expressed as geometric means within quartiles of HEI-2005 scores.. Women with better versus poor quality postdiagnosis diets, as defined by higher HEI-2005 scores (Q4 versus Q1), had lower concentrations of CRP (1.6 mg/L versus 2.5 mg/L), but no significant difference in concentrations of serum amyloid A, leptin, or adiponectin. Among women not engaging in recreational physical activity after diagnosis, better diet quality was associated with lower CRP concentrations (2.5 mg/L versus 5.0 mg/L), but no association was observed among women engaging in any recreational physical activity (1.4 mg/L versus 1.6 mg/L; P heterogeneity = 0.03).. Among breast cancer survivors, a better-quality diet seems to be associated with lower levels of chronic inflammation.. Lower levels of chronic inflammation have been associated with improved survival after breast cancer.

    Topics: Adiponectin; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Cohort Studies; Diet; Female; Humans; Inflammation; Leptin; Middle Aged; Motor Activity; Prognosis; Prospective Studies; Quality of Life; Serum Amyloid A Protein; Surveys and Questionnaires; Survivors

2010
Aromatase expression in leptin-pretreated human breast pre-adipocytes is enhanced by zeranol and suppressed by (-)-gossypol.
    Anticancer research, 2010, Volume: 30, Issue:12

    Obesity is associated with an increased risk of estrogen-dependent breast cancer. Recently, concerns have been raised regarding the role of zeranol (Z), a non-steroidal anabolic growth promoter with potent estrogenic activity widely used in the U.S.A. beef industry, as a possible contributor to an increased incidence of human breast cancer. This study hypothesized that obese individuals may be at greater risk of developing zeranol-induced breast cancer.. The aromatase mRNA expression level of three cell types isolated from adipose tissues were assayed by RT-PCR, and the cell proliferation of primary cultured human normal breast pre-adipocytes (HNBPADs) was investigated using the CellTiter96® non-radioactive method. The effects of Z and gossypol on aromatase expression of leptin-pretreated HNBPADs were evaluated by RT-PCR.. HNBPADs expressed higher aromatase than primary cultured human breast epithelial cells and stromal cells. Z enhanced the mitogenic activity of leptin and increased aromatase expression in HNBPADs. Moreover, (-)-gossypol counteracted Z- and leptin-induced cell proliferation and aromatase expression.. These results suggested that bioactive Z metabolites contained in meat produced from Z-implanted beef cattle may increase estrogen biosynthesis in obese individuals by increasing aromatase expression and estrogen production, which will promote cell sensitivity and increase breast cancer cell growth.

    Topics: Adipocytes; Aromatase; Breast; Breast Neoplasms; Cell Growth Processes; Estrogens, Non-Steroidal; Gossypol; Humans; Leptin; Recombinant Proteins; RNA, Messenger; Stromal Cells; Zeranol

2010
Link between insulin and metabolic disorders in cancer: does leptin play a key role?
    Breast cancer research and treatment, 2009, Volume: 115, Issue:2

    Topics: Breast Neoplasms; Female; Humans; Insulin; Leptin; Metabolic Syndrome; Risk Factors

2009
Leptin utilizes Jun N-terminal kinases to stimulate the invasion of MCF-7 breast cancer cells.
    Clinical & experimental metastasis, 2009, Volume: 26, Issue:3

    In breast tumors, high levels of leptin have been associated with increased incidence of breast cancer metastasis. Breast cancer metastasis is directly associated with breast cancer cell invasion. However, whether leptin could augment breast cancer cell invasion is not known. Here we showed that leptin increased the invasiveness and the matrix metallo-proteinase-2 (MMP-2) activity of the MCF-7 breast cancer cell line. Leptin stimulated the phosphorylation of extracellular signals regulated kinases, signal transducers and activators of transcription 3 and Jun N-terminal kinases (JNK); however, only inhibition of JNK decreased leptin-mediated activation of MMP-2. Furthermore, inhibition of JNK suppressed leptin-mediated breast cancer cell invasion. Here we report the novel findings that leptin increased invasion of breast cancer cells by activating JNK, resulting in increased MMP-2 activity.

    Topics: Breast Neoplasms; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Female; Humans; JNK Mitogen-Activated Protein Kinases; Leptin; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Phosphorylation; Signal Transduction

2009
A pilot study of sampling subcutaneous adipose tissue to examine biomarkers of cancer risk.
    Cancer prevention research (Philadelphia, Pa.), 2009, Volume: 2, Issue:1

    Examination of adipose tissue biology may provide important insight into mechanistic links for the observed association between higher body fat and risk of several types of cancer, in particular colorectal and breast cancer. We tested two different methods of obtaining adipose tissue from healthy individuals. Ten overweight or obese (body mass index, 25-40 kg/m(2)), postmenopausal women were recruited. Two subcutaneous abdominal adipose tissue samples were obtained per individual (i.e., right and left lower abdominal regions) using two distinct methods (method A: 14-gauge needle with incision, versus method B: 16-gauge needle without incision). Gene expression was examined at the mRNA level for leptin, adiponectin, aromatase, interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in flash-frozen tissue, and at the protein level for leptin, adiponectin, IL-6, and TNF-alpha following short-term culture. Participants preferred biopsy method A and few participants reported any of the usual minor side effects. Gene expression was detectable for leptin, adiponectin, and aromatase, but was below detectable limits for IL-6 and TNF-alpha. For detectable genes, relative gene expression in adipose tissue obtained by methods A and B was similar for adiponectin (r = 0.64, P = 0.06) and leptin (r = 0.80, P = 0.01), but not for aromatase (r = 0.37,P = 0.34). Protein levels in tissue culture supernatant exhibited good intra-assay agreement [coefficient of variation (CV), 1-10%], with less agreement for intraindividual agreement (CV, 17-29%) and reproducibility, following one freeze-thaw cycle (CV, >14%). Subcutaneous adipose tissue biopsies from healthy, overweight individuals provide adequate amounts for RNA extraction, gene expression, and other assays of relevance to cancer prevention research.

    Topics: Adiponectin; Aromatase; Biomarkers, Tumor; Biopsy; Breast Neoplasms; Colorectal Neoplasms; Female; Gene Expression; Humans; Interleukin-6; Leptin; Obesity; Overweight; Pilot Projects; Risk Factors; RNA, Messenger; Subcutaneous Fat; Tumor Necrosis Factor-alpha

2009
Circulating levels of leptin, adiposity and breast cancer risk.
    British journal of cancer, 2009, Feb-24, Volume: 100, Issue:4

    The present case-control study was to investigate the relationships of plasma leptin level and anthropometric measures of adiposity with the risk of breast cancer. Questionnaire information, anthropometric measures and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei, between 2004 and 2006. Plasma levels of leptin were measured by RIA. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the associations. Overall, higher leptin concentrations were significantly associated with an increased risk of breast cancer (OR (95% CI) for top vs bottom tertile of leptin was 1.63 (1.07-2.49), P(trend)=0.009). Waist circumference was a significant anthropometric factor for breast cancer in both pre- and postmenopausal women. Furthermore, the associations of leptin with breast cancer risk remained after adjustment for obesity indices. These results suggest that leptin may have an independent role in breast tumorigenesis. Regardless of the impact of circulating leptin, more research is needed to elucidate molecular mechanisms and local leptin levels that are critical for the development of breast cancers.

    Topics: Adiposity; Adult; Aged; Body Mass Index; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Middle Aged; Risk Factors; Surveys and Questionnaires; Taiwan; Waist Circumference

2009
Functional analysis of the -2548G/A leptin gene polymorphism in breast cancer cells.
    International journal of cancer, 2009, Sep-01, Volume: 125, Issue:5

    Leptin is overexpressed in human breast tumors and is produced by breast cancer cells in response to obesity-related stimuli. The leptin promoter polymorphism Lep-2548G/A can be associated with increased leptin secretion by adipocytes and elevated cancer risk. However, molecular mechanisms underlying the link between Lep-2548G/A and breast cancer have never been addressed. Lep-2548G/A is proximal to a binding site for the transcriptional factor Sp1. Furthermore nucleolin, a transcriptional repressor, can bind Sp1 or its consensus site. Consequently, we focused on the impact of Lep-2548G/A on Sp1- and nucleolin-dependent leptin transcription in breast cancer cells. The Lep-2548G/A was identified in a homozygous conformation in BT-474 and SK-BR-3 breast cancer cells, in a heterozygous conformation in MDA-MB-231 cells, and a wild-type Lep-2548G/G sequence was present in MCF-7 and ZR-75-1 cells. The occurrence of Lep-2548A/A and Lep-2548G/A coincided with high and intermediate leptin mRNA expression, respectively, while cells containing Lep-2548G/G expressed low leptin mRNA levels. We demonstrated that the existence of Lep-2548G/A improved efficient recruitment of Sp1 to DNA under insulin treatment, while Sp1 loading on DNA containing Lep-2548G/G was not insulin-dependent. In contrast, nucleolin binding to Lep-2548G/A was downregulated in response to insulin, while it was not regulated on Lep-2548G/G. The presence of Lep-2548G/A was studied in breast cancer epithelial cells by IHC and LCM. Interestingly, all 14 tumors expressing high leptin levels contained Lep-2548A/A. In conclusion, the occurrence of Lep-2548G/A can enhance leptin expression in breast cancer cells via Sp1- and nucleolin-dependent mechanisms and possibly contribute to intratumoral leptin overexpression.

    Topics: Blotting, Western; Body Mass Index; Breast Neoplasms; Chromatin Immunoprecipitation; Genotype; Humans; Hypoglycemic Agents; Insulin; Leptin; Nucleolin; Obesity; Phosphoproteins; Polymorphism, Genetic; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins; RNA, Messenger; Sp1 Transcription Factor; Tumor Cells, Cultured

2009
Effects of adiponectin and leptin co-treatment on human breast cancer cell growth.
    Oncology reports, 2009, Volume: 21, Issue:6

    Obesity is a risk factor for postmenopausal breast cancer (BC), but the specific mechanisms for this relationship are not well understood. Studies on adipocyte-derived adiponectin and leptin reveal opposing effects on BC cell proliferation in vitro, suggesting they may play a role in BC pathogenesis. In the current study we examined effects on proliferation of five BC cell lines treated with varying adiponectin:leptin (A/L) ratios. A decrease in proliferation was noted for MCF-7 and T47-D cells with increasing ratios (2-500), while an increase was seen in similarly treated MDA-MB-231 and MDA-MB-361 cells. For SK-BR-3 cells, an increase was seen at a ratio of 8. We identified differential effects on some pro-mitogenic, survival and apoptosis-related proteins in MCF-7 and T47-D cells treated at an A/L ratio of 100. Specifically, the AKT and MAPK pathways were not activated in MCF-7 cells, but AKT activation occured within 30 min and MAPK activation was sustained at 48 h in T47-D cells. p53 and Bax were elevated in MCF-7, but were below basal in T47-D cells at 30 min. While co-treatment enhanced apoptosis in MCF-7, similar treatment had the opposite effect in T47-D cells. There were no differences in cell cycle distribution between treated or untreated MCF-7 or T47-D, although T47-D cells had a slightly higher proportion in the G1/G0 phase after co-treatment. The effects of A/L ratio on mediating proliferation may have some specificity since the cell lines exhibited different responses. This may explain previous inconsistencies for the relationship of serum leptin with BC. More studies are needed to better understand the complex interactions that exist between these two adipokines.

    Topics: Adiponectin; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Leptin; Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Recombinant Proteins; Signal Transduction; Tumor Suppressor Protein p53

2009
Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women.
    Cancer research, 2009, Jul-01, Volume: 69, Issue:13

    Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.

    Topics: Aromatase; Breast Neoplasms; Colforsin; DNA Primers; Estradiol; Estrogens; Female; Genes, Reporter; Homeostasis; Humans; Leptin; Mammaplasty; Obesity; Polymerase Chain Reaction; Postmenopause; Restriction Mapping; Stromal Cells; Tetradecanoylphorbol Acetate; Transcription Factors; Transfection

2009
Leptin-signaling inhibition results in efficient anti-tumor activity in estrogen receptor positive or negative breast cancer.
    Breast cancer research : BCR, 2009, Volume: 11, Issue:3

    We have shown previously that treatment with pegylated leptin peptide receptor antagonist 2 (PEG-LPrA2) reduced the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor type 2 (VEGFR2) and growth of 4T1-breast cancer (BC) in syngeneic mice. In this investigation, PEG-LPrA2 was used to evaluate whether the inhibition of leptin signaling has differential impact on the expression of pro-angiogenic and pro-proliferative molecules and growth of human estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) BC xenografts hosted by immunodeficient mice.. To test the contribution of leptin signaling to BC growth and expression of leptin-targeted molecules, PEG-LPrA2 treatment was applied to severe immunodeficient mice hosting established ER+ (MCF-7 cells; ovariectomized/supplemented with estradiol) and ER- (MDA-MB231 cells) BC xenografts. To further assess leptin and PEG-LPrA2 effects on ER+ and ER- BC, the expression of VEGF and VEGFR2 (protein and mRNA) was investigated in cell cultures.. PEG-LPrA2 more effectively reduced the growth of ER+ (>40-fold) than ER- BC (twofold) and expression of pro-angiogenic (VEGF/VEGFR2, leptin/leptin receptor OB-R, and IL-1 receptor type I) and pro-proliferative molecules (proliferating cell nuclear antigen and cyclin D1) in ER+ than in ER- BC. Mouse tumor stroma in ER+ BC expressed high levels of VEGF and leptin that was induced by leptin signaling. Leptin upregulated the transcriptional expression of VEGF/VEGFR2 in MCF-7 and MDA-MB231 cells.. These results suggest that leptin signaling plays an important role in the growth of both ER+ and ER- BC that is associated with the leptin regulation of pro-angiogenic and pro-proliferative molecules. These data provide support for the potential use of leptin-signaling inhibition as a novel treatment for ER+ and ER- BC.

    Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Leptin; Mammary Neoplasms, Experimental; Mice; Mice, SCID; Neoplasm Transplantation; Polyethylene Glycols; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

2009
A new therapeutic strategy against cancer: cAMP elevating drugs and leptin.
    Cancer biology & therapy, 2009, Volume: 8, Issue:12

    Topics: Breast Neoplasms; Cyclic AMP; Female; Humans; Leptin

2009
Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies.
    Endocrine-related cancer, 2009, Volume: 16, Issue:4

    Obesity is a risk factor for breast cancer development. A recent hypothesis suggests that the adipokines, adiponectin and leptin, are involved in breast cancer development. This prompted us to investigate the role of adiponectin and leptin in mammary carcinogenesis. Adiponectin receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rt, representing all the isoforms of Ob-R) proteins were detected by immunohistochemistry in in situ ductal carcinoma, invasive ductal malignancy, and healthy adjacent tissue. In addition, mRNA expression of adiponectin, AdipoR1, AdipoR2, leptin, Ob-Rt, and Ob-Rl (the long isoform of Ob-R) was observed in MCF-7 breast cancer cells. Interestingly, leptin mRNA expression was 34.7-fold higher than adiponectin mRNA expression in the MCF-7 cell line. Moreover, adiponectin (10 microg/ml) tended to decrease the mRNA expression of leptin (-36%) and Ob-Rl (-28%) and significantly decreased Ob-Rt mRNA level (-26%). In contrast, leptin treatment (1 microg/ml) significantly decreased AdipoR1 mRNA (-23%). Adiponectin treatment (10 microg/ml) inhibited the proliferation of MCF-7 cells, whereas leptin (1 microg/ml) stimulated the growth of cancer cells. In addition, adiponectin inhibited leptin-induced cell proliferation (both 1 microg/ml). Using microarray analysis, we found that adiponectin reduced the mRNA levels of genes involved in cell cycle regulation (mitogen-activated protein kinase 3 and ATM), apoptosis (BAG1, BAG3, and TP53), and potential diagnosis/prognosis markers (ACADS, CYP19A1, DEGS1, and EVL), whereas leptin induced progesterone receptor mRNA expression. In conclusion, the current study indicates an interaction of leptin- and adiponectin-signaling pathways in MCF-7 cancer cells whose proliferation is stimulated by leptin and suppressed by adiponectin.

    Topics: Adiponectin; Apoptosis; Biomarkers, Tumor; Blotting, Western; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Proliferation; Female; Gene Expression Profiling; Humans; Immunoenzyme Techniques; In Vitro Techniques; Leptin; Neoplasm Invasiveness; Oligonucleotide Array Sequence Analysis; Receptors, Adiponectin; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

2009
Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells.
    Cancer biology & therapy, 2009, Volume: 8, Issue:12

    Elevation of cAMP inhibits the proliferation and expression of transformed phenotype in several cell types, including breast cancer cells. Leptin has been shown to act as a mitogen/survival factor in many types of cancer cells. In the present work, we have studied the impact of cAMP elevation on leptin-induced proliferation of breast cancer cells. Here we report that treatment of estrogen receptor negative human breast cancer cell line MDA-MB-231 with leptin or cAMP elevating agents has positive and negative effects on cell proliferation, respectively. Surprisingly, we find that leptin strongly potentiates the anti-proliferative action of cAMP elevating agents, by concurring to cell cycle arrest at G1 phase and inducing apoptosis. Pretreatment with the PKA inhibitor KT-5720 completely prevented the anti-proliferative effects induced by the combination between leptin and cAMP elevating agents. The above anti-proliferative effects were paralleled by the decrease of cyclin D1 and A and by the increase of inhibitor p27kip1 cell cycle regulating protein levels. In these conditions we found also a strong decrease of anti-apopotic Bcl2 protein levels. Altogether, our data extend the evidence of adenylate cyclase/cAMP/PKA as a growth suppressor system and of leptin as a growth promoting factor in breast cancer cells. Remarkably, our results suggest that when cAMP levels are increased, leptin drives cells towards apoptosis, and that targeting both cAMP levels and leptin signalling might represent a simple novel way for therapeutic intervention in breast cancer.

    Topics: 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Apoptosis; Breast Neoplasms; Carbazoles; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclin-Dependent Kinase Inhibitor p27; Female; G1 Phase; Humans; Leptin; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Signal Transduction

2009
No association between polymorphisms in LEP, LEPR, ADIPOQ, ADIPOR1, or ADIPOR2 and postmenopausal breast cancer risk.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2009, Volume: 18, Issue:9

    There is evidence that adipokines such as leptin and adiponectin may influence breast tumor development. We conducted a nested case-control study using women in the American Cancer Society Cancer Prevention Study II to examine the association between postmenopausal breast cancer and variability in the genes encoding leptin, the leptin receptor, adiponectin, adiponectin receptor 1, and adiponectin receptor 2. Using 648 cases and 659 controls, we found no statistically significant (P < 0.05) associations between breast cancer risk and any of the single nucleotide polymorphisms. Individual odds ratios ranged from 0.93 to 1.06. We found no evidence of effect modification by body mass index, adult weight gain, location of weight gain, or physical activity. Although we cannot rule out that these genes are involved in gene-gene or gene-environment interactions, our results suggest that individual single nucleotide polymorphisms in these genes do not substantially affect postmenopausal breast cancer risk.

    Topics: Adiponectin; Aged; Breast Neoplasms; Case-Control Studies; Female; Genotype; Humans; Leptin; Polymorphism, Single Nucleotide; Postmenopause; Receptors, Adiponectin; Receptors, Leptin; Risk Factors

2009
Obesity and the associated mediators leptin, estrogen and IGF-I enhance the cell proliferation and early tumorigenesis of breast cancer cells.
    Nutrition and cancer, 2009, Volume: 61, Issue:4

    Breast cancer continues to be a major cause of cancer deaths in women. Estrogen, which is also produced by the adipose tissue, is held responsible for the elevated risk of breast cancer in obese women. However, the adipose tissue secrets hormones and adipokines such as leptin and IGF-I and these substances could also contribute to an increased breast cancer risk for obese women. In this study, the impact of obesity on cell proliferation was investigated. The carcinogen 7, 12, dimethylbenz[a]anthracene (DMBA) was administered to normal weight and diet-induced obese female Sprague-Dawley rats. Cell proliferation was evaluated by immunohistological staining of BrdU-incorporation. In the mammary glands and inguinal lymphatic nodes of the obese rats, cell proliferation was significantly increased, indicating a significant influence of obesity on breast cancer. Effects of leptin, estrogen, and IGF-I on the proliferation of MCF-7 cells in vitro were assessed using an MTT assay. Cell culture experiments demonstrated a mitogenic role of these three mediators on cell proliferation. Our data demonstrate a stimulative effect of substances produced by the adipose tissue on breast cancer. Body weight specific cell proliferation suggests that obesity-related adipokines and mediators enhance cell proliferation and increase the risk for breast cancer.

    Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Analysis of Variance; Animals; Body Weight; Breast Neoplasms; Carcinogens; Cell Line, Tumor; Cell Proliferation; Dietary Fats; Disease Models, Animal; Estradiol; Female; Groin; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Leptin; Lymph Nodes; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Obesity; Random Allocation; Rats; Rats, Sprague-Dawley; Time Factors

2009
[Apoptosis resistance induced by leptin and its mechanism in breast cancer cells].
    Zhonghua zhong liu za zhi [Chinese journal of oncology], 2009, Volume: 31, Issue:9

    To explore the apoptosis resistance induced by Leptin and its mechanism in breast cancer cells in vitro.. The leptin-mediated reduction of docetaxel-induced apoptosis in human breast cancer T47D cells was evaluated by TransAM ELISA, MTT and caspase-9 assay. The leptin-promoted survivin expression was analyzed by Western-blot and RT-PCR. The reversing effect of STAT3 knockdown on leptin-induced survivin upregulation was measured by Western-blot and RT-PCR.. Leptin promoted T47D cells proliferation and the inhibitory rate was -63.6%. It reduced docetaxel-induced apoptosis in T47D cells by 31.9%. Leptin at different concentrations promoted survivin protein and mRNA expression in T47D cells. The expression of survivin mRNA was 4.6 fold compared with the T47D cells not treated with leptin(10 nmol/L). The expression of survivin mRNA in T47D cells was 0.55 +/- 0.15 fold after transfected with small interfering RNA (siRNA) of STAT3. The expression of survivin mRNA in STAT3 siRNA group and mock transfected group were 0.56 +/- 0.18 fold and 1.61 +/- 0.22 fold after treated by leptin, respectively. The survivin protein level of T47D mock transfected cells was increased after treated by leptin, but the protein level of T47D transfected with STAT3 siRNA cells were not changed significantly.. Leptin/STAT3 signaling is a novel pathway for up-regulation of survivin expression in breast cancer cells.

    Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Inhibitor of Apoptosis Proteins; Leptin; Microtubule-Associated Proteins; RNA, Messenger; RNA, Small Interfering; Signal Transduction; STAT3 Transcription Factor; Survivin; Transfection; Up-Regulation

2009
Mitogenic activity of zeranol in human breast cancer cells is enhanced by leptin and suppressed by gossypol.
    Anticancer research, 2009, Volume: 29, Issue:11

    The molecular links between breast cancer and obesity have been studied for many years. Obesity significantly increases the incidence rate and chance of morbidity of breast cancer. Leptin, mainly secreted by adipocytes, plays an important role in breast cancer development. Leptin expression is up-regulated in obesity and it can promote breast cancer cell growth. Zeranol is used as an anabolic growth promoter to stimulate cattle growth in the U.S. beef industry. (-)-Gossypol, a natural polyphenolic compound extracted from cottonseed, is an anticancer chemopreventive agent.. Zeranol, leptin and (-)-gossypol were used to investigate MCF-7 Adr cell growth.. Leptin enhanced the sensitivity of MCF-7 Adr cells to zeranol and increased cell growth. Exposure to zeranol may lead to initiation of transformation of normal breast cells to breast preneoplastic cells.. It is suggested that obese individuals may be at greater risk of developing zeranol-induced breast cancer.

    Topics: Anticarcinogenic Agents; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Drug Synergism; Gossypol; Humans; Leptin; Recombinant Proteins; RNA, Messenger; Tumor Suppressor Protein p53; Zeranol

2009
Overexpression of leptin and leptin receptors in breast cancer positively correlates with clinicopathological features.
    Chinese medical journal, 2009, Dec-20, Volume: 122, Issue:24

    Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Receptors, Leptin

2009
The influence of overweight and insulin resistance on breast cancer risk and tumour stage at diagnosis: a prospective study.
    Breast cancer research and treatment, 2009, Volume: 113, Issue:3

    It is hypothesized that insulin resistance and related metabolic factors may influence breast cancer risk, however the epidemiological evidence remains inconclusive. We conducted a case-control study nested in a prospective cohort in Northern Sweden, to clarify the associations of body mass index (BMI), leptin, adiponectin, C-peptide, and glycated haemoglobin (HbA1c) with breast cancer risk. We also investigated whether these associations may be modified by age at diagnosis, tumour stage, and oestrogen and progesterone receptor status. During follow-up, 561 women developed invasive breast cancer and 561 matched controls were selected. Conditional logistic regression was used to calculate odds ratios (OR) as estimates of relative risk, and 95% confidence intervals (CI). The associations of BMI, leptin and HbA1c with breast cancer risk differed significantly according to whether the tumour was diagnosed as stage I or stage II-IV (P (heterogeneity) all <0.05). These factors were significantly inversely associated with risk in the group of stage I tumours, with ORs for top vs. bottom tertile for BMI of 0.48 (95% CI, 0.30-0.78, P (trend) = 0.004); leptin, 0.64 (95% CI, 0.41-1.00, P (trend) = 0.06); and HbA1c, 0.47 (95% CI, 0.28-0.80, P (trend) = 0.005). For stage II-IV tumours, there was a suggestion of an increased risk with higher levels of these factors. There were no significant differences in the associations of BMI, leptin, adiponectin, C-peptide and HbA1c with breast cancer risk in subgroups of age at diagnosis or tumour receptor status. This prospective study suggests that BMI, leptin and HbA1c influence breast tumour initiation and progression.

    Topics: Body Mass Index; Breast Neoplasms; Case-Control Studies; Cohort Studies; Female; Glycated Hemoglobin; Humans; Insulin Resistance; Leptin; Middle Aged; Neoplasm Staging; Overweight; Prospective Studies; Risk Factors

2009
Mammary tumor development from T47-D human breast cancer cells in obese ovariectomized mice with and without estradiol supplements.
    Breast cancer research and treatment, 2009, Volume: 114, Issue:1

    Obesity is a risk factor for postmenopausal breast cancer, particularly for development of estrogen-receptor (ER)-positive tumors. Additionally, obesity is implicated in breast cancer progression. However, few studies address mechanisms of action of how obesity mediates these responses. Our goal was to address how obesity and/or elevated serum leptin affects tumor formation from ER-positive T47-D cells. In Study 1 ovariectomized CD-1 nude female mice were injected with goldthioglucose (GTG) at 0.5 mg/g body weight in saline or the vehicle at 6 weeks of age. At 10 weeks of age mice were inoculated with T47-D cells and implanted with estrogen pellets. In Study 2 mice were injected with 0.3 mg/g GTG or the vehicle. At 10 weeks of age cells were inoculated and mice were implanted with estrogen or placebo pellets. Mice were followed until 30 weeks of age. Some GTG mice became obese and others were non-responders. In Study 1 no mice developed tumors. In Study 2 mice with placebo pellets developed more tumors than mice with estrogen pellets, 50% vs. 13%. GTG-obese mice with placebo pellets had a 100% tumor incidence compared to 50% and 20% for GTG-lean and controls without estrogen. Serum leptin was higher in obese compared to lean mice and adiponectin was not affected by body weight. Adiponectin:leptin ratio was significantly reduced in obese compared to lean mice. Leptin, leptin receptor and signaling protein expression were determined in mammary and tumor tissue. Leptin and STAT3 were most abundant in tumors. These findings suggest that in vivo estrogen suppressed proliferation of T47-D cells but without supplemental estrogen obesity enhanced tumor development. The exact reason for this is not presently clear.

    Topics: Animals; Breast Neoplasms; Disease Models, Animal; Estradiol; Estrogens; Female; Leptin; Mice; Mice, Nude; Mice, Obese; Neoplasm Transplantation; Ovariectomy; Receptors, Estrogen

2009
A novel unidirectional cross-talk from the insulin-like growth factor-I receptor to leptin receptor in human breast cancer cells.
    Molecular cancer research : MCR, 2008, Volume: 6, Issue:6

    Obesity is a major risk factor for the development and progression of breast cancer. Increased circulating levels of the obesity-associated hormones leptin and insulin-like growth factor-I (IGF-I) and overexpression of the leptin receptor (Ob-R) and IGF-I receptor (IGF-IR) have been detected in a majority of breast cancer cases and during obesity. Due to correlations between increased leptin, Ob-R, IGF-I, and IGF-IR in breast cancer, we hypothesized that molecular interactions may exist between these two signaling pathways. Coimmunoprecipitation and immunoblotting showed that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross-signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results show, for the first time, a novel interaction and cross-talk between the IGF-I and leptin receptors in human breast cancer cells.

    Topics: Breast Neoplasms; Cell Line, Tumor; Female; Humans; Insulin-Like Growth Factor I; Leptin; Receptor Cross-Talk; Receptor, IGF Type 1; Receptors, Leptin

2008
Insulin-dependent leptin expression in breast cancer cells.
    Cancer research, 2008, Jun-15, Volume: 68, Issue:12

    Pathologic conditions associated with hyperinsulinemia, such as obesity, metabolic syndrome, and diabetes, seem to increase the risk of breast cancer. Here, we studied molecular mechanisms by which insulin activates the expression of leptin, an obesity hormone that has been shown to promote breast cancer progression in an autocrine or paracrine way. Using MDA-MB-231 breast cancer cells, we found that (a) insulin stimulated leptin mRNA and protein expression, which was associated with increased activation of the leptin gene promoter; (b) insulin increased nuclear accumulation of transcription factors hypoxia inducible factor (HIF)-1alpha and Sp1 and their loading on the leptin promoter; (c) small interfering RNA (siRNA)-mediated knockdown of either HIF-1alpha or Sp1 significantly down-regulated insulin-induced leptin mRNA and protein expression; further inhibition of leptin expression was observed under the combined HIF-1alpha and Sp1 siRNA treatment; (d) inhibition of extracellular signal-regulated kinase (ERK)1/2 and phosphatidylinositol-3-OH kinase (PI-3K) pathways significantly, albeit partially, decreased insulin-dependent leptin mRNA and protein expression, which coincided with reduced association of HIF-1alpha and/or Sp1 with specific leptin promoter regions; and (e) inhibition of ERK1/2 reduced recruitment of both HIF-1alpha and Sp1 to the leptin promoter, whereas down-regulation of PI-3K influenced only HIF-1alpha binding. In summary, our data suggest that hyperinsulinemia could induce breast cancer progression through leptin-dependent mechanisms. In MDA-MB-231 cells, this process requires Sp1- and HIF-1alpha-mediated leptin gene transcription and is partially regulated by the PI-3K and ERK1/2 pathways.

    Topics: Blotting, Western; Breast Neoplasms; Cell Hypoxia; Cell Nucleus; Chromatin Immunoprecipitation; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Humans; Hypoglycemic Agents; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Leptin; Luciferases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Sp1 Transcription Factor; Transcriptional Activation; Tumor Cells, Cultured

2008
Associations among lipids, leptin, and leptin receptor gene Gin223Arg polymorphisms and breast cancer in China.
    Biological trace element research, 2008,Winter, Volume: 126, Issue:1-3

    We evaluated the relationship among the leptin receptor (LEPR) gene Gln223Arg polymorphism, body mass index (BMI), waist and hip circumference ratio (WHR), dietary structure, lifestyle, and other biomarkers with breast cancer and determined whether they could be effective for the prevention and treatment of breast cancer. The Gln223Arg polymorphisms in the LEPR gene were investigated in blood deoxyribonucleic acid (DNA) available for 240 breast cancer cases and 500 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Leptin, insulin were determined by enzyme-linked immunosorbent assays. We found that the serum levels of leptin, insulin, triglyceride (TG), free cholesterol (FCH), apolipoprotain (APO) A1, and BMI were significantly higher in breast cancer cases than the controls, while physical activity was clearly less in breast cancer cases (P < 0.02 approximately P < 0.001, respectively). Moreover, there were significant association between the Gln223Arg genotype and breast cancer risk; homozygotes for AA and heterozygotes for AG,AG + GG genotypes had been proved to increase the risk of breast cancer, and their corresponding odds ratio were 7.14 (95% confidence interval [CI] = 1.92-25.64), 1.33(95% CI = 1.03-2.70), and 2.04 (95% CI = 1.09-3.82). Interestingly, logistic regression analysis showed that LEPR gene Gln223Arg polymorphism and elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB increased the risk of developing breast cancer, respectively. And, it also suggested that LEPR gene Gln223Arg polymorphisms, elevated leptin, insulin, TG, FCH, APOA1, WHR, and reduced APOB should play a major role in the development of breast cancer.

    Topics: Adult; Aged; Body Mass Index; Breast Neoplasms; China; Female; Genotype; Humans; Leptin; Life Style; Lipids; Middle Aged; Polymorphism, Genetic; Receptors, Leptin; Waist-Hip Ratio

2008
Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression.
    The Journal of endocrinology, 2008, Volume: 199, Issue:2

    Obesity is a recently established risk factor for breast cancer incidence and mortality. A characteristic of obesity is elevated circulating levels of adipocyte-derived hormone leptin. Evidence indicates that leptin plays an important role in mammary tumor formation; however, the mechanisms involved are poorly understood. Toward better defining the role of leptin in breast cancer, we describe the identification of leptin-regulated genes in hormone-responsive Michigan Cancer Foundation-7 (MCF-7) human breast cancer cells using a microarray system. More than 64 leptin-regulated genes were identified including those for growth factors, cell cycle regulators, extracellular matrix (ECM) proteins, and genes associated with metastasis. Cell cycle genes up-regulated by leptin include cyclins D and G, cyclin-dependent kinase 2, p21, p27, and p16. Leptin suppressed the expression of transforming growth factor-beta , a cell cycle suppressor. Determining the significance of this effect, treatment of MCF-7 cells with TGFB1 abrogated leptin-stimulated proliferation. Leptin up-regulated the expression of connective tissue growth factor, villin 2, and basigin, factors that are associated with ECM and are known to impact tumor growth. Finally, leptin induced the expression of anti-apoptotic genes BCL2 and survivin, and reduced the expression of apoptotic genes. The effect of leptin on MCF-7 survival was evaluated via TUNEL assay and demonstrated a sixfold reduction in apoptosis in leptin-treated cells, compared with controls. These data suggest leptin promotes mammary tumor growth through multiple mechanisms, including regulating the cell cycle, apoptosis, and by modulating the extracellular environment. The identification of leptin-regulated genes begins to provide mechanistic links into the relationship between obesity and breast cancer incidence and morbidity.

    Topics: Apoptosis; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Leptin; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction

2008
Leptin/HER2 crosstalk in breast cancer: in vitro study and preliminary in vivo analysis.
    BMC cancer, 2008, Oct-22, Volume: 8

    Obesity in postmenopausal women is associated with increased breast cancer risk, development of more aggressive tumors and resistance to certain anti-breast cancer treatments. Some of these effects might be mediated by obesity hormone leptin, acting independently or modulating other signaling pathways. Here we focused on the link between leptin and HER2. We tested if HER2 and the leptin receptor (ObR) can be coexpressed in breast cancer cell models, whether these two receptors can physically interact, and whether leptin can transactivate HER2. Next, we studied if leptin/ObR can coexist with HER2 in breast cancer tissues, and if presence of these two systems correlates with specific clinicopathological features.. Expression of ObR, HER2, phospho-HER2 was assessed by immunoblotting. Physical interactions between ObR and HER2 were probed by immunoprecipitation and fluorescent immunostaining. Expression of leptin and ObR in breast cancer tissues was detected by immunohistochemistry (IHC). Associations among markers studied by IHC were evaluated using Fisher's exact test for count data.. HER2 and ObR were coexpressed in all studied breast cancer cell lines. In MCF-7 cells, HER2 physically interacted with ObR and leptin treatment increased HER2 phosphorylation on Tyr 1248. In 59 breast cancers, the presence of leptin was correlated with ObR (the overall association was about 93%). This result was confirmed both in HER2-positive and in HER2-negative subgroups. The expression of leptin or ObR was numerically more frequent in larger (> 10 mm) tumors.. Coexpression of HER2 and the leptin/ObR system might contribute to enhanced HER2 activity and reduced sensitivity to anti-HER2 treatments.

    Topics: Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leptin; Obesity; Postmenopause; Protein Binding; Receptor Cross-Talk; Receptor, ErbB-2; Receptors, Leptin; Risk Factors; Transcriptional Activation

2008
Association between alcohol intake and serum sex hormones and peptides differs by tamoxifen use in breast cancer survivors.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2008, Volume: 17, Issue:11

    To measure the association between alcohol intake and 11 hormones and peptides in postmenopausal breast cancer survivors and to evaluate whether this association differs by tamoxifen use.. Self-reported alcohol intake was assessed via food frequency questionnaire on average 30 months post-breast cancer diagnosis in 490 postmenopausal women from three western states. Concurrently, a fasting blood sample was obtained for assay of estrone, estradiol, free estradiol, testosterone, free testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), leptin, C-peptide, insulin-like growth factor-I (IGF-I), and IGF-binding protein-3. Adjusted means of these hormones and peptides were calculated for categories of alcohol intake, overall and stratified by tamoxifen use.. The association between alcohol intake and serum hormone and peptide levels differed by tamoxifen use. We found statistically significant inverse associations between alcohol intake and both leptin and SHBG values but only among tamoxifen users. In women not using tamoxifen, we found a positive association between alcohol intake and DHEAS but no association in tamoxifen users.. Tamoxifen may modify the association between alcohol intake and serum hormones and peptides. The significant associations found for DHEAS and SHBG are in a direction considered unfavorable for breast cancer prognosis. Postmenopausal breast cancer survivors may benefit from decreasing their alcohol intake.

    Topics: Alcohol Drinking; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cross-Sectional Studies; Dehydroepiandrosterone; Female; Gonadal Steroid Hormones; Humans; Leptin; Middle Aged; Peptides; Postmenopause; Sex Hormone-Binding Globulin; Surveys and Questionnaires; Survivors; Tamoxifen

2008
Balance of adiponectin and leptin modulates breast cancer cell growth.
    Cell research, 2008, Volume: 18, Issue:11

    Topics: Adiponectin; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Female; Humans; Leptin

2008
Adiponectin and leptin expression in primary ductal breast cancer and in adjacent healthy epithelial and myoepithelial tissue.
    Histopathology, 2008, Volume: 53, Issue:4

    Topics: Adiponectin; Breast Neoplasms; Carcinoma, Ductal, Breast; Epithelial Cells; Female; Humans; Leptin

2008
Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor.
    Cancer research, 2008, Dec-01, Volume: 68, Issue:23

    Obesity is an independent risk factor for breast cancer, and obese breast cancer patients exhibit a higher risk for larger tumor burden and increased metastasis. Obesity, as associated with metabolic syndrome, results in an increase in circulating insulin-like growth factor (IGF), which acts as a mitogen. In addition, higher plasma level of adipocytokine leptin is associated with obesity. In the present study, we show that cotreatment with leptin and IGF-I significantly increases proliferation as well as invasion and migration of breast cancer cells. We found a novel bidirectional crosstalk between leptin and IGF-I signaling; IGF-I induced phosphorylation of leptin receptor (Ob-Rb) and leptin induced phosphorylation of IGF-I receptor (IGF-IR), whereas cotreatment induced synergistic phosphorylation and association of Ob-Rb and IGF-IR along with activation of downstream effectors, Akt and extracellular signal-regulated kinase. Leptin increased phosphorylation of IGF signaling molecules insulin-receptor substrate (IRS)-1 and IRS-2. Interestingly, we found that leptin and IGF-I cotreatment synergistically transactivated epidermal growth factor receptor (EGFR), depending on the proteolytic release of EGFR ligands, as the broad-spectrum matrix metalloproteinase inhibitor GM6001 could inhibit this effect. Using clinically relevant EGFR inhibitors, erlotinib and lapatinib, we found that inhibition of EGFR activation effectively inhibited leptin- and IGF-I-induced invasion and migration of breast cancer cells. Taken together, these data suggest a novel bidirectional crosstalk between leptin and IGF-I signaling that transactivates EGFR and promotes the metastatic properties as well as invasion and migration of breast cancer cells. Our findings indicate the possibility of using EGFR inhibitors erlotinib and lapatinib to counter the procancerous effects of leptin and IGF-I in breast cancers.

    Topics: Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Drug Synergism; ErbB Receptors; Erlotinib Hydrochloride; Humans; Insulin-Like Growth Factor I; Lapatinib; Leptin; Neoplasm Invasiveness; Quinazolines; Receptor Cross-Talk; Receptor, IGF Type 1; Receptors, Leptin; Signal Transduction; Transcriptional Activation

2008
Mechanism of leptin expression in breast cancer cells: role of hypoxia-inducible factor-1alpha.
    Oncogene, 2008, Jan-17, Volume: 27, Issue:4

    We reported previously that the obesity hormone leptin is overexpressed in breast cancer biopsies. Here, we investigated molecular mechanisms involved in this process, focusing on conditions that are associated with obesity, that is, hyperinsulinemia and induction of hypoxia. By using quantitative real-time PCR, immunofluorescent detection of proteins and enzyme-linked immunosorbent assays, we found that treatment of MCF-7 breast cancer cells with high doses of insulin or the hypoxia-mimetic agent CoCl2, or culturing the cells under hypoxic conditions significantly increased the expression of leptin mRNA and protein. Notably, the greatest leptin mRNA and protein expression were observed under combined hyperinsulinemia and hypoxia or hypoxia-mimetic treatments. Luciferase reporter assays suggested that increased leptin synthesis could be related to the activation of the leptin gene promoter. DNA affinity precipitation and chromatin immunoprecipitation experiments revealed that insulin, CoCl2 and/or hypoxia treatments augmented nuclear accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and increased its interaction with several upstream leptin regulatory sequences, especially with the proximal promoter containing four hypoxia-response elements and three GC-rich regions. By using reverse chromatin precipitation, we determined that loading of HIF-1alpha on the proximal leptin promoter concurred with the recruitment of p300, the major HIF coactivator, suggesting that the HIF/p300 complex is involved in leptin transcription. The importance of HIF-1alpha in insulin- and CoCl2-activated leptin mRNA and protein expression was confirmed using RNA interference.

    Topics: Active Transport, Cell Nucleus; Binding Sites; Breast Neoplasms; Cell Hypoxia; Cell Nucleus; Cobalt; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Leptin; p300-CBP Transcription Factors; Promoter Regions, Genetic; Protein Binding; Transcriptional Activation; Tumor Cells, Cultured

2008
Leptin augments proliferation of breast cancer cells via transactivation of HER2.
    The Journal of surgical research, 2008, Volume: 149, Issue:1

    Excessive fat mass is a risk factor for postmenopausal breast cancer. Leptin, a fat cell-derived peptide hormone, elicits a growth-stimulating effect in breast cancer cells with leptin receptor expression, although the leptin-induced signal in malignant cells is not fully understood. Here, we found that exogenous leptin induced tyrosine phosphorylation of HER2 in SKBR3 cells, which showed marked overexpression of HER2. Phosphorylation of HER2 was detected at 2 min and continued up to 120 min after the start of stimulation. Leptin-induced HER2 phosphorylation was partially reduced by an epidermal growth factor receptor inhibitor, AG1478, or a Janus-activated kinase inhibitor, AG490. Leptin also induced phosphorylation of extracellular signal-regulated kinase 1/2, which was mostly abrogated by a HER2 tyrosine kinase inhibitor, AG825. In a proliferation assay, addition of 500 ng/mL leptin increased the proliferation of SKBR3, which was totally inhibited by AG825. Collectively, our data suggest that leptin can transactivate HER2 through both epidermal growth factor receptor and Janus-activated kinase 2 activation, which can cause the growth of breast cancer cells with HER2 overexpression.

    Topics: Breast Neoplasms; Cell Proliferation; Female; Genes, erbB-2; Hormones; Humans; Leptin; Phosphorylation; Receptors, Leptin; Transcriptional Activation; Tumor Cells, Cultured

2008
Fat may fuel breast cancer growth.
    Journal of the National Cancer Institute, 2008, Mar-05, Volume: 100, Issue:5

    Topics: Adipose Tissue; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Disease-Free Survival; Estrogens; Exercise; Female; Humans; Inflammation; Insulin; Insulin-Like Growth Factor I; Leptin; Neoplasms; Obesity; Overweight; Recurrence; Risk Assessment; Risk Factors; United Kingdom; Weight Gain

2008
Leptin and leptin receptor involvement in cancer development: a study on human primary breast carcinoma.
    Oncology reports, 2008, Volume: 19, Issue:4

    Obesity is associated with an increased risk of breast cancer. Leptin, a hormone synthesised essentially by adipose tissue, may be involved in cancer development. We examined the expression of leptin and leptin receptor (Ob-R) in human primary breast cancer and adjacent non-cancerous tissue. We also analysed their relationships with histological variables such as the oestrogen and progesterone receptors, Ki67 proliferation factor and tumour size. The expressions of leptin and Ob-R were investigated by immunohistochemical staining in 35 primary breast cancers and 17 adjacent non-cancerous tissues. Samples and histological features were obtained from the Anti-Cancer Centre. Expressions of leptin and Ob-R were detected in, respectively, 85 and 75% of the primary breast cancer cases studied. The expression of leptin was significantly correlated with Ob-R detection (p=0.008). In addition, Ob-R expression in primary breast carcinoma was positively correlated with oestrogen receptor expression (p=0.028) and tumour size (p=0.045) but not with Ki67 or progesterone receptor expressions. However, the expression of leptin showed no statistical correlation with these variables. First, the co-expression of leptin and Ob-R in primary breast cancer shows that leptin acts on mammary tumour cells via an autocrine pathway. Second, the co-expression of Ob-R and oestrogen receptors suggests a possible interaction between leptin and oestrogen systems to promote breast carcinogenesis. Finally, the fact that Ob-R expression was positively correlated with tumour size may point to a potential role of leptin as a growth factor and of Ob-R as a new prognostic factor.

    Topics: Adult; Aged; Breast Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Middle Aged; Receptors, Leptin

2008
Microvascular transplantation of adipose tissue and serum level of adipocyte products.
    Aesthetic plastic surgery, 2008, Volume: 32, Issue:3

    Microvascular transplantation of subcutaneous adipose tissue is an essential step in reconstructive surgery after breast carcinoma. Serum levels of adipose tissue products may serve as indicators for transplant function. This study aimed to determine serum leptin and tumor necrosis factor (TNF)-alpha plasma levels pre-, intra-, and postoperatively in 20 patients undergoing reconstructive breast surgery and in 7 women undergoing abdominoplasty operation. In the patients undergoing reconstructive breast surgery, the serum leptin levels decreased intraoperatively from 14.5 +/- 13.1 to 9.1 +/- 7.3 ng/ml, a decrease of 63%. An increase in serum leptin levels to 13.5 +/- 12.7 ng/ml (93% of the initial value) was found on postoperative day 1. This was paralleled by similar changes in the plasma levels of TNF-alpha (preoperatively, 20 +/- 7.3 pg/ml; intraoperatively, 17 +/- 11.4 pg/ml; postoperatively, 21 +/- 10.8 pg/ml). In the patients undergoing abdominoplasty, plasma leptin and TNF-alpha levels decreased intraoperatively (20% and 27%, respectively) and postoperatively (44% and 27%, respectively). The results of our pilot study indicate that a postoperative increase in the level of serum leptin after reconstructive breast surgery may be related to successful transplant function.

    Topics: Abdomen; Adipocytes; Adipose Tissue; Adult; Breast Neoplasms; Carcinoma; Female; Humans; Leptin; Mammaplasty; Microcirculation; Microsurgery; Pilot Projects; Plastic Surgery Procedures; Postoperative Care; Tumor Necrosis Factor-alpha

2008
leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3.
    The Journal of biological chemistry, 2007, May-04, Volume: 282, Issue:18

    Numerous epidemiological studies documented that obesity is a risk factor for breast cancer development in postmenopausal women. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease state. In this study, we analyzed the role of leptin and the molecular mechanism(s) underlying its action in breast cancer cells that express both short and long isoforms of leptin receptor. Leptin increased MCF7 cell population in the S-phase of the cell cycle along with a robust increase in CYCLIN D1 expression. Also, leptin induced Stat3-phosphorylation-dependent proliferation of MCF7 cells as blocking Stat3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation. Using deletion constructs of CYCLIN D1 promoter and chromatin immunoprecipitation assay, we show that leptin induced increase in CYCLIN D1 promoter activity is mediated through binding of activated Stat3 at the Stat binding sites and changes in histone acetylation and methylation. We also show specific involvement of coactivator molecules, histone acetyltransferase SRC1, and mediator complex in leptin-mediated regulation of CYCLIN D1 promoter. Importantly, silencing of SRC1 and Med1 abolished the leptin induced increase in CYCLIN D1 expression and MCF7 cell proliferation. Intriguingly, recruitment of both SRC1 and Med1 was dependent on phosphorylated Stat3 as AG490 treatment inhibited leptin-induced recruitment of these coactivators to CYCLIN D1 promoter. Our data suggest that CYCLIN D1 may be a target gene for leptin mediated growth stimulation of breast cancer cells and molecular mechanisms involve activated Stat3-mediated recruitment of distinct coactivator complexes.

    Topics: Acetylation; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Chromatin Immunoprecipitation; Cyclin D; Cyclins; Endodeoxyribonucleases; Female; Histone Acetyltransferases; Histones; Humans; Leptin; Methylation; Obesity; Postmenopause; Promoter Regions, Genetic; Protein Modification, Translational; S Phase; STAT3 Transcription Factor; Tyrphostins

2007
Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels.
    The Journal of steroid biochemistry and molecular biology, 2007, Volume: 104, Issue:1-2

    The adipocytokine leptin has recently been shown to enhance the expression of aromatase via promoter II and I.3 using an AP-1 motif. Thus, we evaluated the correlation between plasma leptin concentrations and total body aromatization (TBA) as well as plasma levels of estrone (E(1)), estradiol (E(2)) and estrone sulfate (E(1)S) in postmenopausal breast cancer patients. Twenty-two postmenopausal women with metastatic breast cancer, participating in tracer studies for the measurement of total body aromatization (TBA) in vivo, were available. In addition, blood samples for plasma estrogens and leptin measurements were available from another 22 breast cancer patients and 114 healthy postmenopausal women participating in the mammography-screening program. Values for TBA varied from 1.46 to 4.72% while plasma leptin levels ranged from 1.83 to 95.51 ng/ml in the same group of patients. All plasma estrogen levels were in the normal range expected for postmenopausal women. We found a significant correlation between pretreatment leptin levels and TBA (r(s) 0.452, P=0.01). In contrast, basal levels of TBA did not correlate to body mass index (BMI) in the same group of patients. Plasma leptin levels correlated to plasma levels of estradiol (r(s) 0.659, P=0.007), and estrone sulfate (r(s) 0.562, P=0.01) in the group of breast cancer patients (n=44) as well as in the group of healthy postmenopausal women (estradiol, r(s) 0.363, P< or =0.001, estrone sulfate r(s) 0.353, P< or =0.001). In conclusion, we found plasma leptin levels to correlate to TBA in breast cancer patients and to plasma levels of estradiol and estrone sulfate in breast cancer patients as well as in healthy postmenopausal females. These findings suggest that leptin may influence on aromatase activity in vivo, providing a possible link between body weight and plasma estrogen levels as well as breast cancer risk.

    Topics: Aged; Androstenedione; Aromatase; Aromatase Inhibitors; Body Mass Index; Breast Neoplasms; Estradiol; Estrone; Female; Humans; Leptin; Middle Aged; Postmenopause

2007
Signs of proinflammatory/genotoxic switch (adipogenotoxicosis) in mammary fat of breast cancer patients: role of menopausal status, estrogens and hyperglycemia.
    International journal of cancer, 2007, Aug-01, Volume: 121, Issue:3

    The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFalpha and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by (3)H(2)O release from (3)H-1beta-androstenedione. In the postmenopausal BC patients, NO and TNFalpha production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre- and postmenopausal BC patients. This condition is likely being maintained through estrogen- and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis.

    Topics: Adipose Tissue; Adult; Aged; Aged, 80 and over; Aromatase; Breast Neoplasms; Cytochrome P-450 Enzyme System; Estrogens; Female; Humans; Hyperglycemia; Inflammation; Leptin; Macrophages; Mammary Glands, Human; Middle Aged; Postmenopause; Premenopause

2007
Diet-induced obesity and mammary tumor development in relation to estrogen receptor status.
    Cancer letters, 2007, Aug-18, Volume: 253, Issue:2

    Leptin enhances proliferation of estrogen receptor (ER)-positive breast cancer cells in vitro. Here, we compared mammary tumor (MT) formation from ER-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cells in athymic mice fed a High-Fat diet to elevate serum leptin. Neither body weight, diet or serum leptin levels impacted MT latency, burden or tumor grade. However, protein expression in mammary fat pads exhibited elevated PCNA and Cyclin D1 while in MTs, Ob-Rb, IGF-IR, Bcl-2, and Bax were lower in Low-Fat versus High-Fat mice. In conclusion, diet rather than serum leptin impacted breast cancer cell tumor metabolism.

    Topics: Animals; Breast Neoplasms; Diet; Dietary Fats; Female; Humans; Leptin; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Obesity; Proteins; Receptors, Estrogen; Tumor Cells, Cultured

2007
Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression.
    Cancer research, 2007, Apr-01, Volume: 67, Issue:7

    Leptin, a cytokine mainly produced by adipocytes, seems to play a crucial role in mammary carcinogenesis. In the present study, we explored the mechanism of leptin-mediated promotion of breast tumor growth using xenograft MCF-7 in 45-day-old female nude mice, and an in vitro model represented by MCF-7 three-dimensional cultures. Xenograft tumors, obtained only in animals with estradiol (E(2)) pellet implants, doubled control value after 13 weeks of leptin exposure. In three-dimensional cultures, leptin and/or E(2) enhanced cell-cell adhesion. This increased aggregation seems to be dependent on E-cadherin because it was completely abrogated in the presence of function-blocking E-cadherin antibody or EGTA, a calcium-chelating agent. In three-dimensional cultures, leptin and/or E(2) treatment significantly increased cell growth, which was abrogated when E-cadherin function was blocked. These findings well correlated with an increase of mRNA and protein content of E-cadherin in three-dimensional cultures and in xenografts. In MCF-7 cells both hormones were able to activate E-cadherin promoter. Mutagenesis studies, electrophoretic mobility shift assay, and chromatin immunoprecipitation assays revealed that cyclic AMP-responsive element binding protein and Sp1 motifs, present on E-cadherin promoter, were important for the up-regulatory effects induced by both hormones on E-cadherin expression in breast cancer MCF-7 cells. In conclusion, the present study shows how leptin is able to promote tumor cell proliferation and homotypic tumor cell adhesion via an increase of E-cadherin expression. This combined effect may give reasonable emphasis to the important role of this cytokine in stimulating primary breast tumor cell growth and progression, particularly in obese women.

    Topics: Animals; Breast Neoplasms; Cadherins; Cell Adhesion; Cell Growth Processes; Cyclic AMP Response Element-Binding Protein; Disease Progression; DNA, Neoplasm; Egtazic Acid; Estradiol; Estrogen Receptor alpha; Female; Humans; Leptin; Mice; Mice, Nude; Promoter Regions, Genetic; RNA, Messenger; Sp1 Transcription Factor; Transfection; Up-Regulation

2007
Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status.
    International journal of oncology, 2007, Volume: 30, Issue:6

    Obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin, a cytokine synthesized in adipose tissue, has been implicated as a link between obesity and breast cancer. In the present study, the effects of leptin on cell proliferation and proteins associated with leptin signaling and/or breast cell growth were investigated in ER-positive, MCF-7, T47-D and MDA-MB-361, and ER-negative, MDA-MB-231 and SK-BR-3, breast cancer cell lines. MDA-MB-361 and SK-BR-3 also overexpress HER2/neu. For proliferation assays, 96-well plates were used and for protein determinations cells were synchronized in 6-well plates for 18-24 h in serum-free medium. Leptin was added at 0, 5, 10, 25, 50 and 100 ng/ml for 24 and 48 h. For Western blot analyses, protein extracts were probed for Ob-Rb, Ob-R, leptin, Jak2, PI3K, Stat3, p-Stat3, PCNA, cyclin D1, Cox-2, VEGF, Bcl-2, Bcl-xL, Bax, insulin, IGF-I, IGFBP3, IGF-IRalpha, aromatase, CYP1A1 and CYP1B1. Overall, except for MCF-7 cells, leptin stimulated proliferation in all lines. MCF-7 cells expressed higher levels of Ob-Rb, Jak2, PI3K, Stat3 and p-Stat3 in a dose-dependent manner to 50 ng/ml at 24 h; and IGF-IRalpha increased at 24 h. Cyclin D1 and Cox-2 levels increased with leptin treatment. Higher CYP1B1 expression was observed at both 24 and 48 h. In MDA-MB-231 cells, p-Stat3 and Bcl-xL were increased at 48 h; whereas PCNA and cyclin D1 expression increased in leptin-treated cells at 24 and 48 h. In T47-D cells, Jak2 and Stat3 were elevated at higher leptin concentrations at 24 and 48 h. However, p-Stat3 and PCNA demonstrated an increase only in 48-h leptin-treated cells. Furthermore, cyclin D1 exhibited higher expression at both 24 and 48 h, while Bcl-xL expression was lower with increasing concentrations of leptin at 48 h. In MDA-MB-361 cells, Ob-Rb and VEGF increased at 24 and 48 h; whereas PI3K, Stat3, PCNA and insulin levels increased in leptin-treated MDA-MB-361 cells after 48 h. Bcl-2 and IGF-IRalpha were decreased at 24 h and a dose-dependent increase at 48 h was noted. Higher expression of CYP1B1 was observed with leptin for 24 h. In SK-BR-3 cells, Ob-R increased at both 24 and 48 h. A similar trend was found for IGF-I and IGFBP3 expression. Higher levels of Jak2 and PI3K were observed after 24 h. Interestingly, there was a gradual increase of leptin expression at 24 h, but a gradual decrease at 48 h in relation to the dose of leptin. In contrast, PCNA and IGF-IRalpha showed a

    Topics: Blotting, Western; Breast Neoplasms; Cell Line; Cell Proliferation; Female; Humans; Immunohistochemistry; Leptin; Obesity; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Leptin; Risk Factors

2007
[Association among lipids, leptin and leptin receptor polymorphisms with risk of breast cancer].
    Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi, 2007, Volume: 28, Issue:2

    To evaluate the association between serum level of leptin and leptin receptor gene (LEPR) polymorphism and patients with breast cancer.. LEPR G1n223Arg polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 94 patients with breast cancer and 128 healthy controls. The level of leptin were analyzed by enzyme linked immunosorbent assay.. In univariate regression analyses, we found serum level of leptin and LEPR Gin223Arg genotype polymorphism were significantly higrer than those of the controls (P < 0.05-0.001, respectively). Through multivariable analyses, we found that increased risk estimates for breast cancer were among those with leptin level (OR = 1.53, 95% CI: 1.13-2.07, P = 0.006), LEPR Gin223Arg genotype (OR = 4.87, 95%CI:1.30-18.22, P = 0.019), WHR (OR = 3.68, 95% CI: 1.34-10.11, P = 0.011).. Results from this study suggested that LEPR Gln233Agr polymorphism, the elevated WHR and serum level of leptin might be correlated with increased risk of breast cancer.

    Topics: Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Genetic Predisposition to Disease; Humans; Leptin; Lipids; Polymorphism, Genetic; Receptors, Leptin; Risk

2007
Adipocytokines and breast cancer risk.
    Chinese medical journal, 2007, Sep-20, Volume: 120, Issue:18

    Many researches suggested that obesity increased the risk of breast cancer, but the mechanism was currently unknown. Adipocytokines might mediate the relationship. Our study was aimed to investigate the relationship between serum levels of resistin, adiponectin and leptin and the onset, invasion and metastasis of breast cancer.. Blood samples were collected from 80 newly diagnosed, histologically confirmed breast cancer patients and 50 age-matched healthy controls. Serum levels of resistin, adiponectin and leptin were determined by enzyme-linked immunosorbent assays (ELISA); fasting blood glucose (FBG), lipids, body mass index (BMI), and waist circumference (WC) were assayed simultaneously.. Serum levels of adiponectin ((8.60 +/- 2.92) mg/L vs (10.37 +/- 2.81) mg/L, P = 0.001) and HDL-c were significantly decreased in breast cancer patients in comparison to controls. Serum levels of resistin ((26.35 +/- 5.36) microg/L vs (23.32 +/- 4.75) microg/L, P = 0.000), leptin ((1.35 +/- 0.42) microg/L vs (1.06 +/- 0.39) microg/L, P = 0.003), FBG and triglyceride (TG) in breast cancer patients were increased in contrast to controls, respectively. However, we did not find the significant difference of the serum levels of resistin, adiponectin and leptin between premenopausal breast cancer patients and healthy controls (P = 0.091, 0.109 and 0.084, respectively). The serum levels of resistin, adiponectin and leptin were significantly different between patients with lymph node metastasis (LNM) and those without LNM (P = 0.001, 0.000 and 0.006, respectively). The stepwise regression analysis indicated that the tumor size had the close correlation with leptin (R(2) = 0.414, P = 0.000) and FBG (R(2) = 0.602, P = 0.000). Logistic regression analysis showed that reduced serum levels of adiponectin (OR: 0.805; 95% CI: 0.704 - 0.921; P = 0.001), HDL (OR: 0.087; 95% CI: 0.011 - 0.691, P = 0.021), elevated leptin (OR: 2.235; 95% CI: 1.898 - 4.526; P = 0.004) and resistin (OR: 1.335; 95% CI: 1.114 - 2.354; P = 0.012) increased the risk for breast cancer; Reduced serum levels of adiponectin (OR: 0.742; 95% CI: 0.504 - 0.921; P = 0.003) and elevated leptin (OR: 2.134; 95% CI: 1.725 - 3.921; P = 0.001) were associated with lymph node metastasis of breast cancer.. The decreased serum adiponectin levels and increased serum resistin and leptin levels are risk factors of breast cancer. The low serum adiponectin levels and high serum leptin levels are independent risk factors for metastasis of cancer. The association between obesity and breast cancer risk might be explained by adipocytokines.

    Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Logistic Models; Lymphatic Metastasis; Middle Aged; Resistin; Risk Factors

2007
The roles of serum leptin concentration and polymorphism in leptin receptor gene at codon 109 in breast cancer.
    Oncology, 2007, Volume: 72, Issue:1-2

    We investigated the relationship between serum leptin concentrations and polymorphism of the leptin receptor gene and breast cancer.. Serum leptin concentrations were measured by enzyme-linked immunosorbent assay in 47 women with invasive breast cancer compared with 41 age-matched controls without cancer. Genomic DNA was extracted from peripheral blood leukocytes. Genotyping of the leptin receptor gene at codon 109 (LEPR-109) was performed by polymerase chain reaction-restriction fragment length polymorphism.. Patients with breast cancer had a higher mean serum leptin concentration than women in the control group, but the difference was not statistically significant. Among those with breast cancer, the serum leptin concentration was higher in women with high-grade cancers (p = 0.020). The LEPR-109RR genotype was more frequent in premenopausal patients with tumors larger than 2 cm (p = 0.039) and in premenopausal women who were overweight (p = 0.029). Among patients with the LEPR-109RR genotype, higher mean serum leptin concentrations were present in those with triple-negative cancers (p = 0.048).. Our study suggests an association between serum leptin concentration and tumor progression. LEPR-109 polymorphism in premenopausal women appears to be associated with obesity and tumor progression.

    Topics: Adult; Breast Neoplasms; Case-Control Studies; Disease Progression; Female; Genotype; Humans; Leptin; Middle Aged; Obesity; Polymorphism, Genetic; Premenopause; Receptors, Leptin

2007
[Properties of mammary fat in breast cancer patients: topographic, systemic and environmental factors].
    Voprosy onkologii, 2007, Volume: 53, Issue:5

    Breast cancer course may be influenced by a profile of steroids and peptides produced by mammary fat. The study was concerned with assessment of hormonal (leptin and adiponectin production, adipocyte diameter and aromatase level) and progenotoxic factors which characterize DNA damage (8-OHdG) and such cancer promoters as tumor necrosis (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate reactive products (TRP), macrophage/histiocyte infiltration, estrogen 4-hydroxylase expression (CYP1B1) in mammary fat located 1.5-2 cm or not less than 5 cm away from tumor edge. Thirty-three pairs of mammary fat samples from 23 menopausal and 10 cycling patients were used. Closer proximity of mammary fat involved intensified biosynthesis of estrogens (as shown by aromatase level) and their conversion to catechol derivatives (as shown by CYP1B1 concentration) as well as accumulation of 8-OH-dG. Smoking and hyperglycemic patients and those with considerable mammary fat volume revealed accumulations of anti-inflammatory and progenotoxic cytokines (IL-6 or TNF-alpha). Hence, hormonal/progenotoxic ratio in mammary fat can be identified both by topographic, systemic and environmental factors.

    Topics: 8-Hydroxy-2'-Deoxyguanosine; Adipokines; Adiponectin; Adipose Tissue; Adult; Aged; Aromatase; Aryl Hydrocarbon Hydroxylases; Breast; Breast Neoplasms; Cytochrome P-450 CYP1B1; Deoxyguanosine; DNA Damage; Estrogens; Female; Humans; Interleukin-6; Leptin; Menopause; Middle Aged; Nitric Oxide; Premenopause; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

2007
Dietary soy and tea combinations for prevention of breast and prostate cancers by targeting metabolic syndrome elements in mice.
    The American journal of clinical nutrition, 2007, Volume: 86, Issue:3

    The prevalence of metabolic syndrome is high and is increasing in parallel with increasing incidences of breast and prostate cancers. The combination of soy with tea was shown to have synergistic effects on preventing breast and prostate tumors, but the effects of soy and tea combinations on metabolic syndrome-related elements have not been investigated.. We aimed to determine the effects of soy and tea components, alone and in combination, on abdominal adipose mass and serum concentrations of adipokines, growth factors, and sex hormones in male and female mice.. Male and female FVB/N mice were treated with soy, tea components, or both. Food intake and body weight were monitored weekly. At the end of the experiment, abdominal white adipose tissue was weighed, and serum concentrations of biomarkers were measured.. Whole teas, but not the tea polyphenol extracts, significantly reduced abdominal white adipose tissue by 43-60% in female mice and by 65-70% in male mice. The combination of soy phytochemical concentrate and green tea reduced serum insulin-like growth factor-I concentrations in both male and female mice in a synergistic manner. The soy phytochemical concentrate and tea combinations reduced serum estrogen concentrations in female mice in a synergistic manner. Soy phytochemical concentrate and teas also significantly reduced serum leptin concentrations in both male and female mice and testosterone concentrations in male mice.. Further research is warranted to investigate whether soy and tea combinations may prevent breast or prostate cancer in a synergistic manner in part by alleviating metabolic disorders.

    Topics: Abdominal Fat; Adiponectin; Animals; Breast Neoplasms; Diet; Drug Synergism; Estrogens; Female; Humans; Insulin-Like Growth Factor I; Leptin; Male; Metabolic Syndrome; Mice; Prostatic Neoplasms; Random Allocation; Soybean Proteins; Tea; Testosterone

2007
Expression of leptin and its receptor in female breast cancer in relation with selected apoptotic markers.
    Folia histochemica et cytobiologica, 2007, Volume: 45 Suppl 1

    Leptin and its receptor may be engaged in pathogenesis of breast cancer among various human tumors. In vitro investigations showed leptin-mediated escalation of estrogen synthesis and boosted activity of estrogen receptor ERalpha. Furthermore, leptin induced growth of malignant cells, counteracted apoptosis and stimulated cell migration as well as overexpression of angiogenic factors and degrading enzymes that split network of intercellular matrix. On the other side, leptin has been reported to favor apoptosis, lately. Proapoptotic effect of leptin action was revealed in interstitial cells of bone marrow and adipocytes. Our past reports provide evidences for overexpression of leptin and its receptor in breast cancer in comparison with benign mammary lesions. In current study we aimed at assessment of eventual relationships between leptin, leptin receptor and selected protein regulators of apoptosis in breast cancer. We applied immunohistochemistry for leptin, leptin receptor, anti-apoptotic Bcl-2 and Bcl-xL as well as pro-apoptotic Bak and Bax expression assessment in 106 cases of human breast cancers. The immunoreaction was graded and statistically evaluated. Expression of leptin was positively correlated with Bcl-xL, Bak and Bax (p<0.001, r=0.614; p<0.001, r=0.518; p<0.001, r=0.511, respectively). Statistical significances were noted between expression of leptin receptor and Bcl-xL or Bax (p=0.011, r=0.210; p<0.001, r=0.313, respectively). No correlation was encountered between leptin and Bcl-2, either leptin receptor and Bcl-2 or leptin receptor and Bak. On the basis of obtained results, leptin system could interfere in balance among expressions of pro- and anti-apoptotic proteins and regulate cell turnover and--by means of it--facilitate breast cancer progression.

    Topics: Adult; Aged; Aged, 80 and over; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Immunohistochemistry; Leptin; Middle Aged; Receptors, Leptin

2007
Relationships among serum leptin, leptin receptor gene polymorphisms, and breast cancer in Korea.
    Cancer letters, 2006, Jun-08, Volume: 237, Issue:1

    Leptin plays an important role in the regulation of body fat homeostasis, and potential associations of leptin receptor gene (LEPR) polymorphisms with obesity have been suggested. Obesity is considered to relate to breast cancer. We assessed the role of leptin in relation to breast cancer. We measured the serum leptin concentrations of 45 Korean pre-treatment patients with breast cancer and 45 age-matched controls. By direct sequencing, we investigated four leptin receptor gene (LEPR) polymorphisms at codons 109, 223, 656, and 1019. There was no significant difference between the mean leptin concentrations of the patient and control groups in both pre- and post-menopausal women. The frequencies of the wild-type for LEPR codons 109, 223, and 1019 were very low. No increased risk estimate was found for the four LEPR polymorphisms. Our results indicate that it is difficult to explain breast cancer on the basis of serum leptin concentrations or polymorphisms in the LEPR gene.

    Topics: Adult; Breast Neoplasms; Case-Control Studies; Female; Gene Expression Regulation, Neoplastic; Gene Frequency; Genotype; Humans; Korea; Leptin; Middle Aged; Polymorphism, Genetic; Receptors, Cell Surface; Receptors, Leptin

2006
Serum adiponectin and leptin levels in Taiwanese breast cancer patients.
    Cancer letters, 2006, Jun-08, Volume: 237, Issue:1

    The role of two adipocytokines, adiponectin and leptin, in Taiwanese breast cancer patients remains to be determined. In this study, we analyzed the correlations between the serum levels of adiponectin and leptin and the various clinicopathological parameters in 100 newly diagnosed, histologically confirmed breast cancer patients and 100 controls. We found serum levels were decreased significantly for adiponectin in the breast cancer patients, in comparison to controls (Student t-test, P=0.003), while serum levels were increased significantly for leptin in the breast cancer patients in comparison to controls (Student t-test, P=0.025). Leptin/adiponectin (L/A ratio) were increased significantly in the breast cancer patients, in comparison to controls (Student t-test, P=0.009). Among the clinicopathological parameters, estrogen receptor, progesterone receptor, HER2/neu, lymph node metastasis, tumor stage, and tumor grade all showed no effect on the serum levels of adiponectin and leptin. BMI was negatively and positively correlated to serum adiponectin and leptin levels, respectively (Spearman's correlation, r=-0.333 and 0.323, respectively; P<0.001 for both). Intriguingly, serum L/A ratio disclosed a positive correlation to tumor size (r=0.21, P=0.036). In summary, our results suggest that low serum adiponectin levels and high serum leptin levels are associated with an increased risk for breast cancer. Also, independent of the effect of BMI, the increased serum ratio of L/A may indicate the presence of aggressive breast cancers.

    Topics: Adiponectin; Adult; Age of Onset; Aged; Aged, 80 and over; Blood Glucose; Body Mass Index; Breast Neoplasms; Demography; Female; Humans; Leptin; Middle Aged; Neoplasm Invasiveness; Taiwan

2006
High expression of leptin receptor mRNA in breast cancer tissue predicts poor prognosis for patients with high, but not low, serum leptin levels.
    International journal of cancer, 2006, Mar-15, Volume: 118, Issue:6

    The association of mRNA expression levels of leptin receptors (long isoform: Lep-R(L) and short isoform: Lep-R(S)) in breast cancer tissue with patient prognosis was studied with special reference to the serum leptin level or the leptin mRNA level in tumor tissue. Lep-R(L), Lep-R(S) and leptin mRNA levels in breast cancer tissue (n = 91) were determined with a real-time PCR assay, and serum leptin levels in breast cancer patients (n = 67) with an enzyme-linked immunosorbent assay. Neither Lep-R(L) nor Lep-R(S) mRNA levels in tumor tissue were significantly associated with patient prognosis, but both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly (p < 0.01) associated with a poor prognosis. Multivariate analysis showed that a high level of both Lep-R (L) and Lep-R (S) mRNA in tumor tissue was a significant risk factor, independent of other risk factors. The subset analysis demonstrated that both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors were significantly associated with a poor prognosis for the subset of patients with high serum leptin or high intratumoral leptin mRNA levels but not in the subset of patients with low serum leptin or low intratumoral leptin mRNA levels. The association between both intratumoral Lep-R(L) and Lep-R(S) mRNA high tumors and a poor prognosis in the presence of high serum leptin or high intratumoral leptin mRNA levels seems to suggest that the leptin and Lep-R(L)/Lep-R(S) pathways are implicated in the growth stimulation of breast tumors. The well-established finding that obesity serves as a risk factor for relapse in breast cancer patients may thus be partially explained by the high serum leptin level seen in obese women.

    Topics: Adult; Body Mass Index; Breast Neoplasms; Disease-Free Survival; Drug Therapy; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mastectomy; Middle Aged; Multivariate Analysis; Prognosis; Protein Isoforms; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger

2006
Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients.
    Cancer, 2006, Feb-15, Volume: 106, Issue:4

    The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia.. Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy.. A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men.. Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome.

    Topics: Adiponectin; Aged; Breast Neoplasms; Cachexia; Colonic Neoplasms; Female; Ghrelin; Humans; Leptin; Male; Middle Aged; Peptide Hormones; Sex Factors; Weight Loss

2006
Interrelationships between serum leptin, IGF-1, IGFBP3, C-peptide and prolactin and breast cancer risk in young women.
    Breast cancer research and treatment, 2006, Volume: 98, Issue:2

    Epidemiologic evidence suggests obese premenopausal women experience a reduced risk of breast cancer. The mechanism underlying this protection is not fully understood although it is well documented that abdominal obesity may impair ovulatory function and reduce gonadal steroidogenesis. We measured levels of several metabolic markers that are modified by obesity [measured by body mass index (BMI, (weight (kg)/height (m2)))] and play a role in the reproductive axis, including, leptin, insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP3), C-peptide and prolactin in 233 cases and 251 controls participating in a retrospective study of breast cancer in young women conducted in the Seattle/Puget Sound region between 1990 and 1992. Consistent with the finding of a reduced risk with increasing BMI, risks declined with leptin levels, although to a lesser degree with odds ratios (OR) for the highest vs. lowest quartile of BMI=0.34 (95% C.I. 0.3-0.8) and for leptin=0.71 (95% C.I. 0.5-1.3). IGF-I, IGFBP3, C-peptide and prolactin were not related to breast cancer risk in a dose-dependent manner. With the possible exception of leptin, our findings do not suggest that these markers explain the breast cancer protection provided by obesity in premenopausal women.

    Topics: Adult; Body Mass Index; Breast Neoplasms; C-Peptide; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Prolactin; Risk Factors

2006
Leptin and leptin receptor polymorphisms are associated with increased risk and poor prognosis of breast carcinoma.
    BMC cancer, 2006, Feb-20, Volume: 6

    Leptin (LEP) has been consistently associated with angiogenesis and tumor growth. Leptin exerts its physiological action through its specific receptor (LEPR). We have investigated whether genetic variations in LEP and LEPR have implications for susceptibility to and prognosis in breast carcinoma.. We used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the LEP and LEPR genes in 308 unrelated Tunisian patients with breast carcinoma and 222 healthy control subjects. Associations of the clinicopathologic parameters and these genetic markers with the rates of the breast carcinoma-specific overall survival (OVS) and the disease free survival (DFS) were assessed using univariate and multivariate analyses.. A significantly increased risk of breast carcinoma was associated with heterozygous LEP (-2548) GA (OR = 1.45; P = 0.04) and homozygous LEP (-2548) AA (OR = 3.17; P = 0.001) variants. A highly significant association was found between the heterozygous LEPR 223QR genotype (OR = 1.68; P = 0.007) or homozygous LEPR 223RR genotype (OR = 2.26; P = 0.001) and breast carcinoma. Moreover, the presence of the LEP (-2548) A allele showed a significant association with decreased disease-free survival in breast carcinoma patients, and the presence of the LEPR 223R allele showed a significant association with decreased overall survival.. Our results indicated that the polymorphisms in LEP and LEPR genes are associated with increased breast cancer risk as well as disease progress, supporting our hypothesis for leptin involvement in cancer pathogenesis.

    Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Case-Control Studies; Disease Progression; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Neovascularization, Pathologic; Polymorphism, Genetic; Prognosis; Receptors, Cell Surface; Receptors, Leptin; Risk Assessment; Tunisia

2006
Leptin receptor expression and cell signaling in breast cancer.
    International journal of oncology, 2006, Volume: 28, Issue:4

    Obesity is considered a risk factor for many cancers, including breast cancer. Our laboratory has previously shown that leptin is mitogenic in many cancer cell lines, including breast. Information regarding the effects of high leptin levels on leptin receptor expression and signaling is lacking. The purpose of this study was to characterize leptin receptor expression in response to leptin in breast cancer cells. In addition, SOCS-3 expression (a leptin inducible inhibitor of leptin signaling), plus MAPK and PI3K signaling, were examined to determine their role in leptin-induced cell proliferation. Breast cancer cell lines, ZR75-1 and HTB-26, were treated with 0, 4, 40 or 80 ng/ml of leptin. Multiplex RT-PCR was performed to determine relative mRNA expression levels of the human short (huOB-Ra) or long (huOB-Rb) leptin receptor isoforms, or SOCS-3. MAPK and PI3K signaling was analyzed by phosphorylation of ERK and Akt, respectively, via Western blotting. Cell proliferation and inhibitor studies were analyzed by MTT assay. HTB-26 and ZR75-1 both expressed huOB-Ra, huOB-Rb and SOCS-3 mRNA; however, mRNA expression levels generally remained unchanged over time with leptin treatment. MAPK and PI3K pathways were activated in the presence of leptin over time. MAPK and PI3K inhibitors significantly blocked leptin-induced proliferation. Higher levels of circulating leptin contribute to breast cancer proliferation by activation of the MAPK and PI3K signaling pathways involved in cell growth and survival. The mitogenic effects of leptin are not a consequence of altered leptin receptor or SOCS-3 mRNA expression.

    Topics: Blotting, Western; Breast Neoplasms; Butadienes; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromones; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mitogen-Activated Protein Kinases; Morpholines; Nitriles; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors

2006
Increased expression of leptin and the leptin receptor as a marker of breast cancer progression: possible role of obesity-related stimuli.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006, Mar-01, Volume: 12, Issue:5

    Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions.. The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines.. Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells.. Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol.

    Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Case-Control Studies; Cell Hypoxia; Disease Progression; Estradiol; Female; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Middle Aged; Neoplasms; Obesity; Receptors, Cell Surface; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

2006
Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2006, Apr-01, Volume: 12, Issue:7 Pt 1

    Leptin and obesity are clearly related, and obesity is associated with an increased risk of breast cancer. We therefore measured the expression of leptin and its two main receptor isoforms, OBR-L and OBR-S, in 322 breast cancers. We analyzed their relations with the classical prognostic factors and with survival to establish their links with breast cancer.. The expression of leptin and its receptors was quantified by real-time reverse transcription-PCR, using TaqMan fluorogenic probes and an ABI PRISM 7700 sequence detector system (Applied Biosystems, Courtaboeuf, France). TATA box binding protein was used to normalize expression. The human breast cancer cell, SK-BR-3, expressing the three targets, was chosen as the calibrator sample (i.e., target expression = 1).. All the tumors expressed both receptors, and 318 of 322 expressed leptin. These three variables correlated positively with each other and with estradiol and progesterone receptors, whereas they correlated negatively with histoprognostic grading and tumor diameter. OBR-L/OBR-S expression was inversely correlated with progesterone receptors. Patients with elevated OBR-S expression had longer relapse-free survival (P = 0.008), whereas high OBR-L/OBR-S was associated with a shorter relapse-free survival (P = 0.05). In Cox multivariate analyses, OBR-S maintained its prognostic value (P = 0.02; relative risk, 0.51).. This study shows that (a) almost all of the breast cancers coexpress leptin and its two main isoforms of receptors, suggesting that the human epithelial breast cancer cells respond to leptin acting via an autocrine pathway; (b) high expression levels of leptin and leptin receptors are biological markers of a more differentiated phenotype; and that (c) OBR-S is an independent prognostic factor.

    Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leptin; Middle Aged; Multivariate Analysis; Phenotype; Prognosis; Receptors, Cell Surface; Receptors, Leptin; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Analysis

2006
Leptin-induced growth of human ZR-75-1 breast cancer cells is associated with up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21WAF1/CIP1.
    Breast cancer research and treatment, 2006, Volume: 98, Issue:2

    Obesity has been recognized as a risk factor for breast cancer. Adipocyte-derived leptin may play as a paracrine regulator on the growth of breast cancer cells. Expression of both leptin and its OB-Rb receptor was detected in human breast cancer ZR-75-1 cells and further induced by leptin, suggesting that both expression and message mediation of leptin were autoregulated by itself. With cell counting and MTT assay, we had observed leptin stimulated ZR-75-1 growth in dose- and time-dependent manners. To study what steps of cell cycle progression leptin may involve in, we analyzed cell-cycle profile with flow cytometric analysis, mRNA and protein expressions of four cell-cycle regulators with RT-PCR and Western blotting analysis. Under the treatment of leptin, the G1 arrest of cells was reduced accompanied with up-regulation of G1 phase-specific cyclin D1 and proto-oncogene c-Myc, but down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/CIP1) and tumor suppressor p53. Furthermore, JAK2 inhibitor AG490, PI3K/Akt inhibitor Wortmannin, and MEK/ERK1/2 inhibitor PD98059 were efficiently prevented leptin-promoted cell growth. Effect of cooperation between leptin and estrogen on ZR-75-1 growth had been observed. Collectively, the results showed that the proliferative effect of leptin on ZR-75-1 was associated with the up-regulation of cyclin D1 and c-Myc and down-regulation of tumor suppressor p53 and p21(WAF1/CIP1) plausibly through a hypothesized JAK2-PI3K/Akt-MEK/ERK pathway. The leptin- and OB-Rb-expressing capability of ZR-75-1 created a possible autocrine control of leptin, in which signal could be effectively amplified by itself, on cell growth.

    Topics: Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; Estrogens; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation; Genes, myc; Humans; Leptin; MAP Kinase Kinase Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins c-akt; Tumor Suppressor Protein p53; Up-Regulation

2006
[Endocrine-metabolic peculiarities in women of reproductive age with hyperplastic processes of cervix and mammary glands].
    Georgian medical news, 2006, Issue:134

    The aim of our investigation was the detection of endocrine-metabolic disorders in patients with hyperplastic processes of endomyometrium, uterine cervix and mammary glands. 88 patients of reproductive age with several gynaecological complaints have been investigated. 72 patients with hyperplastic processes in endomyometrium, uterine cervix (hyperplasia, polyposis, myoma) and mammary glands (fibroadenomatosis, adenomatosis) were selected in main group. Control group consisted of 16 patients without any hyperplastic processes of reproductive organs. Metabolic syndrome in main group was revealed in 28% of cases, in control - 18,8% (chi(2)=3,95, p=0,047); insulin resistance - 37,5% and 18,7% (chi(2)=4,59, p=0,033), respectively; obesity - 52,8% and 25,0% (chi(2)=4,05, p=0,045), respectively; dyslipidemia - 52,8% and 0,0%; hypertension - 26,4% and 12,5% (chi(2)=1,88, p=NS), respectively. Blood leptin level in main group was - 13,7+/-10,9 ng/ml, and in control - 5,0+/-2,9 ng/ml (p=0,005). Our results suggest that metabolic syndrome and its components significantly influences the formation of hyperplastic processes of endomyometrium, uterine cervix and mammary glands. Blood leptin level is significantly increased in patients with hyperplastic pathologies.

    Topics: Adult; Breast Neoplasms; Cervix Uteri; Endocrine System Diseases; Female; Humans; Hyperplasia; Leptin; Mammary Glands, Human; Metabolic Syndrome; Reproduction; Uterine Cervical Neoplasms

2006
Plasma levels of leptin and mammographic density among postmenopausal women: a cross-sectional study.
    Breast cancer research : BCR, 2006, Volume: 8, Issue:5

    Obesity has been linked to increased risk of breast cancer in postmenopausal women. Increased peripheral production of estrogens has been regarded as the main cause for this association, but other features of increased body fat mass may also play a part. Leptin is a protein produced mainly by adipose tissue and may represent a growth factor in cancer. We examined the association between leptin plasma levels and mammographic density, a biomarker for breast cancer risk.. We included data from postmenopausal women aged 55 and older, who participated in a cross-sectional mammography study in Tromsø, Norway. Mammograms, plasma leptin measurements as well as information on anthropometric and hormonal/reproductive factors were available from 967 women. We assessed mammographic density using a previously validated computer-assisted method. Multiple linear regression analysis was applied to investigate the association between mammographic density and quartiles of plasma leptin concentration. Because we hypothesized that the effect of leptin on mammographic density could vary depending on the amount of nondense or fat tissue in the breast, we also performed analyses on plasma leptin levels and mammographic density within tertiles of mammographic nondense area.. After adjusting for age, postmenopausal hormone use, number of full-term pregnancies and age of first birth, there was an inverse association between leptin and absolute mammographic density (P(trend) = 0.001). When we additionally adjusted for body mass index and mammographic nondense area, no statistically significant association between plasma leptin and mammographic density was found (P(trend) = 0.16). Stratified analyses suggested that the association between plasma leptin and mammographic density could differ with the amount of nondense area of the mammogram, with the strongest association between leptin and mammographic absolute density in the stratum with the medium breast fat content (P(trend) = 0.003, P for interaction = 0.05).. We found no overall consistent association between the plasma concentration of leptin and absolute mammographic density. Although weak, there was some suggestion that the association between leptin and mammographic density could differ with the amount of fat tissue in the breast.

    Topics: Adipose Tissue; Aged; Breast Neoplasms; Cross-Sectional Studies; Female; Humans; Leptin; Mammography; Middle Aged; Postmenopause; Risk

2006
[Hormonal and progenotoxic properties of mammary fat in pre- and postmenopausal cancer patients].
    Voprosy onkologii, 2006, Volume: 52, Issue:5

    Since breast cancer may emerge both before and after menopause onset, relevant forms of the disease show marked biological and clinical differences. Intrinsic properties of mammary fat located in the vicinity of tumor, which play a definitive role in stromal-epithelial interactions, are an important factor of development of such differences. The DNA damage promoting hormonal (leptin and adiponectin production, aromatase activity) and progenotoxic. The properties of mammary fat such as formation of tumor necrosis factor, interleukin-6, nitric oxide, malonic aldehyde, macrophage/histiocyte infiltration and estrogen 4-hydroxylase expression, were studied in mammary fat tissue of 95 patients with receptor-positive or receptor-negative breast tumors (reproductive--25, menopausal--70). It was found that progenotoxic properties might somewhat predominate, as far as differences in parameters and pathways are concerned, both in menopausal and still cycling patients. Hence, progenotoxic damage which represents mammary fat tissue status is perhaps modified by a number of genetic and mitochondrial factors. It may exert unfavorable effect on the course of the disease within a fairly wide period.

    Topics: Adiponectin; Adipose Tissue; Aromatase; Aryl Hydrocarbon Hydroxylases; Breast Neoplasms; Cytochrome P-450 CYP1B1; DNA Damage; Female; Histiocytes; Humans; Interleukin-6; Leptin; Macrophages; Malondialdehyde; Middle Aged; Mutagenicity Tests; Neoplasms, Hormone-Dependent; Nitric Oxide; Postmenopause; Premenopause; Receptors, Estrogen; Tumor Necrosis Factor-alpha

2006
Metabolic and hormonal profiles: HDL cholesterol as a plausible biomarker of breast cancer risk. The Norwegian EBBA Study.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005, Volume: 14, Issue:1

    Low serum high-density lipoprotein cholesterol (HDL-C) is an important component of the metabolic syndrome and has recently been related to increased breast cancer risk in overweight and obese women. We therefore questioned whether serum HDL-C might be a biologically sound marker of breast cancer risk. We obtained cross-sectional data among 206 healthy women ages 25 to 35 years who participated in the Norwegian EBBA study. We included salivary ovarian steroid concentrations assessed by daily samples throughout one entire menstrual cycle, metabolic profile with measures of adiposity [body mass index (BMI) and truncal fat percentage], serum concentrations of lipids and hormones (insulin, leptin, testosterone, dehydroepiandrostendione sulfate, insulin-like growth factor-I, and its principal binding protein), and mammographic parenchymal pattern. We examined how components of the metabolic syndrome, including low serum HDL-C, were related to levels of hormones, and free estradiol concentration in particular, and studied predictors of mammographic parenchymal patterns in regression models. In women with BMI > or = 23.6 kg/m(2) (median), overall average salivary estradiol concentration dropped by 2.4 pmol/L (0.7 pg/mL; 13.2% change in mean for the total population) by each 0.33 mmol/L (12.8 mg/dl; 1SD) increase in serum HDL-C (P = 0.03; P(interaction) = 0.03). A subgroup of women characterized by both relatively high BMI (> or =23.6 kg/m(2)) and high serum LDL-C/HDL-C ratio (> or = 2.08; 75 percentile) had substantially higher levels of salivary estradiol by cycle day than other women (P = 0.001). BMI was the strongest predictor of overall average estradiol with a direct relationship (P< 0.001). Serum HDL-C was inversely related to serum leptin, insulin, and dehydroepiandrostendione sulfate (P < 0.001, P < 0.01, and P < 0.05, respectively). There was a direct relationship between breast density and healthy metabolic profiles (low BMI, high serum HDL-C; P < 0.001) and salivary progesterone concentrations (P < 0.05). Our findings support the hypothesis that low serum HDL-C might reflect an unfavorable hormonal profile with, in particular, increased levels of estrogens and gives further clues to biomarkers of breast cancer risk especially in overweight and obese women.

    Topics: Adult; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; Cholesterol, LDL; Cross-Sectional Studies; Female; Gonadal Steroid Hormones; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; Lipids; Mammography; Norway; Regression Analysis; Saliva; Surveys and Questionnaires

2005
Serum levels of leptin, insulin, and lipids in relation to breast cancer in china.
    Endocrine, 2005, Volume: 26, Issue:1

    Epidemiological studies have found obesity to be a risk factor for women's breast cancer. The present study was to investigate whether there is a relationship between serum levels of leptin, insulin, and lipids and breast cancer incidence, in order to find experimental evidence that would be helpful in the diagnosis and prevention of breast cancer. Blood samples were collected from 130 patients with mammary disease and 103 healthy control subjects. Serum leptin, insulin, and lipids were determined by radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISA), and Biochemistry Auto-analyzer, respectively. The data analysis was performed by use of the SPSS10.0 computer software. We found that the serum levels of leptin, insulin, and triglyceride (TG) were clearly higher in patients with breast cancer than in patients with benign breast disease and healthy controls, while serum HDL-C levels were lower in breast cancer patients (p < 0.03). Moreover, serum leptin levels were significantly correlated with BMI (body mass index) among three groups, whereas serum insulin levels were unrelated to BMI among three groups. Furthermore, the serum levels of leptin and insulin were not associated with menopausal status in patients with mammary disease (p > 0.05); however, the serum levels of F-Chol, T-Chol, TG, LDL-C, and APOB were significant higher in postmenopausal cases than those in premenopausal cases (p < 0.025). Interestingly, logistic regression analysis showed that subjects with elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C displayed increased risk of developing breast cancer than those with the normal levels, respectively. In conclusion, the present study suggested that aberrant serum levels of leptin, insulin, and lipids might play an important role in carcinogenesis of breast cancer. The elevated serum levels of leptin, insulin, TG, APOA1, and reduced level of serum HDL-C may be correlated with increased risk of breast cancer, suggesting that one way of preventing breast cancer would be carried out by controlling the intake of food.

    Topics: Adult; Apolipoprotein A-I; Apolipoproteins B; Breast Neoplasms; China; Cholesterol; Female; Humans; Insulin; Leptin; Lipids; Logistic Models; Middle Aged; Triglycerides

2005
BRCA1 mutation, leptin and estrogen levels in breast cancer patients.
    European journal of gynaecological oncology, 2005, Volume: 26, Issue:2

    Pre- and postmenopausal patients with breast cancer were screened for mutation of the BRCAI gene and estrogens and leptin levels were measured. In postmenopausal BRCA1 mutation carriers, leptin levels were significantly lower and correlated with the body mass index (BMI). No significant difference in leptin levels was revealed between pre- and postmenopausal patients. Our findings suggest the existence of an alternative mechanism responsible for carcinogenesis in breast cancer patients with a genetic background.

    Topics: Adolescent; Adult; Body Mass Index; Breast Neoplasms; Estradiol; Estrone; Female; Genes, BRCA1; Humans; Leptin; Middle Aged; Mutation; Postmenopause; Premenopause

2005
Leptin: a proliferative factor for breast cancer? Study on human ductal carcinoma.
    Biochemical and biophysical research communications, 2005, Sep-02, Volume: 334, Issue:3

    Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFalpha and IL-1beta). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic beta cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study.

    Topics: Adult; Aged; Aged, 80 and over; Breast; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Female; Humans; Leptin; Middle Aged

2005
The relationship between blood leptin level and bone density is specific to ethnicity and menopausal status.
    The Journal of laboratory and clinical medicine, 2005, Volume: 146, Issue:1

    Leptin, the obesity hormone, has been linked to bone mineralization and tumorigenesis. In addition, both bone mineral density (BMD) and postmenopausal breast cancer are associated with obesity, but the interrelationships between obesity, leptin, BMD, and breast cancer are not yet clear. In particular, there is little published research comparing white and black women in terms of these variables. We obtained blood specimens for leptin analysis from a group of 320 breast cancer patients and controls with an ethnic composition of 49% white women and 51% black women. Distal and proximal radial BMD (DBMD and PBMD) were measured by dual-energy X-ray absorptiometry, and age- and ethnicity-specific standardized scores (Z-scores) were calculated for bone density. Blood leptin levels were determined by radioimmunoassay. Blood leptin level was not linked to breast cancer risk. Leptin levels were significantly higher in black women than in white women and were also significantly higher in obese and overweight women than in normal-weight women. Black women weighed more and had a higher body mass index (BMI) than white women. After controlling for BMI, leptin was correlated with DBMD ( r = .17; P < .05) and PBMD ( r = .21; P < .05) in whites, but not in blacks. Leptin was also correlated with both distal and proximal Z-scores in postmenopausal women ( r = .14 and .13; P < .05). Thus leptin may be a predictor for BMD in a population that is prone to have a low BMD, and this relationship is independent of the effect of body weight on leptin levels. Our results suggest that ethnicity and menopausal status should be considered when comparing results from different studies.

    Topics: Black People; Body Mass Index; Body Weight; Bone Density; Breast Neoplasms; Female; Hormone Replacement Therapy; Humans; Leptin; Menopause; Middle Aged; White People

2005
Is leptin a mediator of adverse prognostic effects of obesity in breast cancer?
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2005, Sep-01, Volume: 23, Issue:25

    Leptin, an adipocyte-derived cytokine that is elevated in obesity, has been associated with carcinogenesis, tumor migration and invasion, enhancement of angiogenesis, and increased aromatase activity. It has been suggested that leptin may mediate adverse prognostic effects of obesity in breast cancer.. Four hundred seventy-one women with surgically resected T1-3, N0-1, M0 breast cancer were studied. Leptin was assayed in stored fasting blood specimens obtained before adjuvant therapy. Women were followed prospectively for distant disease-free survival (DDFS) and overall survival (OS).. Patients ranged from 26 to 74 years of age, and staging was as follows: T1 = 262, T2 = 151, T3 = 23, TX = 35, N0 = 323, and N1 = 148. Estrogen receptor was positive in 286 patients, and progesterone receptor was positive in 259 patients. One hundred forty-five patients received adjuvant chemotherapy, 146 received adjuvant tamoxifen, 46 received both, and 134 received neither. Mean leptin was 15.2 +/- 10.1 ng/mL. Univariately, leptin was associated with OS (overall P = .049; P = .014 postmenopausal). Leptin was not associated with DDFS overall or in any menopausal subgroup (P > or = .19). In multivariate Cox modeling, leptin was not significantly associated with DDFS or OS (P = .11 and 0.075, respectively). Adjustment for insulin or body mass index further reduced the association of leptin with outcome.. Although leptin is strongly correlated with obesity and insulin, we could not show that it is independently associated with prognosis in early-stage breast cancer. Because we cannot rule out modest prognostic effects, we recommend additional research to explore this potential association, particularly in postmenopausal women.

    Topics: Adult; Aged; Breast Neoplasms; Cohort Studies; Disease-Free Survival; Female; Humans; Hypoglycemic Agents; Insulin; Leptin; Middle Aged; Neoplasm Staging; Obesity; Predictive Value of Tests; Prognosis; Receptors, Estrogen

2005
Relationship of obesity and physical activity with C-peptide, leptin, and insulin-like growth factors in breast cancer survivors.
    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005, Volume: 14, Issue:12

    Obese and physically inactive breast cancer patients may have poorer survival compared with lighter weight and more active women. Several obesity-related and physical activity-related hormones and peptides may explain this association, including insulin, leptin, insulin-like growth factor-I (IGF-I), and IGF-binding protein-3. Few studies have examined the associations between obesity, physical activity, and these hormones/peptides among breast cancer survivors.. To determine whether obesity and physical activity are associated with insulin, IGFs, and leptin levels in a population-based sample of 710 women diagnosed with in situ to stage IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study.. We collected a blood sample and information on physical activity among women diagnosed 2 to 3 years earlier using an interview-administered questionnaire. Trained staff measured weight. C-peptide, leptin, and IGFs were assayed by RIA. Mean hormone levels within body mass index and physical activity categories were adjusted for confounders using analysis of covariance methods.. We observed higher C-peptide (P for trend = 0.0001) and leptin (P for trend = 0.0001) levels and lower IGF-I levels (P for trend = 0.0001) with higher levels of body mass index. We observed lower C-peptide (P for trend = 0.001) and leptin (P for trend = 0.001) levels and higher IGF-I (P for trend = 0.0037) and IGF-binding protein-3 (P for trend = 0.055) levels with higher levels of physical activity.. Increasing physical activity and decreasing body fat may be a reasonable intervention approach toward changing insulin and leptin, thereby potentially influencing breast cancer prognosis.

    Topics: Adult; Analysis of Variance; Biomarkers, Tumor; Body Mass Index; Breast Neoplasms; C-Peptide; Chi-Square Distribution; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Leptin; Middle Aged; Motor Activity; Obesity; Prospective Studies; Survivors

2005
Breast cancer size in postmenopausal women is correlated with body mass index and androgen serum levels.
    Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology, 2004, Volume: 18, Issue:1

    Our objective was to investigate the effects of age, weight, body mass index (BMI), sex steroid receptor status and serum parameters such as estradiol, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS) and leptin on the size of a malignant breast tumor. A total of 62 premenopausal (median age 44.0 years) and 151 postmenopausal (median age 59.1 years) Caucasian women undergoing lumpectomy or mastectomy for invasive breast cancer were examined. Patient parameters (age, body weight, BMI), tumor parameters (tumor size, estrogen and progesterone receptor status) and serum parameters (estradiol, testosterone, androstenedione, DHEAS and leptin) were measured. An increase of BMI and DHEAS levels was associated with larger tumors by partial correlation (rp) analysis (rp = 0.418, p = 0.008; and rp = 0.329, p = 0.041, respectively), whereas higher androstenedione levels corresponded with smaller tumors. Furthermore, BMI, androstenedione and DHEAS levels were correlated: an increase in DHEAS was associated with higher androstenedione serum concentrations (rp = 0.603, p < 0.001), but was also associated with a lower BMI (rp = -0.378, p < 0.001). BMI and androstenedione serum concentrations were also associated (rp = 0.242, p = 0.009), thus closing a circle of mutual interactions. We conclude that, although breast cancer progression is characterized by autonomous growth that has become independent of growth regulatory mechanisms, tumor size at the time of detection is influenced by a complex system of counter-regulatory feedback mechanisms that might represent the body's physiological attempt to control the size of a malignant tumor.

    Topics: Adult; Androstenedione; Body Mass Index; Breast Neoplasms; Dehydroepiandrosterone Sulfate; Estradiol; Female; Humans; Leptin; Menopause; Middle Aged; Testosterone

2004
Adipocyte expression and circulating levels of leptin increase in both gynaecological and breast cancer patients.
    International journal of oncology, 2004, Volume: 24, Issue:6

    Leptin is a hormone involved in the regulation of body weight and sexual maturation. We previously reported that cancer cachexia was associated with reduced or normal levels of leptin. Here we investigate whether leptin levels are related to cachetic or hormonal status. Circulating leptin and its mRNA from adipose tissue were measured in 87 patients with gynaecological and breast cancers and related to tumour, cachexia and hormonal markers. We found that leptin protein increased in patients with these tumours due to higher mRNA levels. In patients with ovarian cancer, the increased leptin levels were associated with higher circulating follicle-stimulating hormone (FSH). The higher leptin concentrations in patients with endometrial and portio tumours were related to an increase in tissue estrogen receptor (ER) and progesterone receptor (PGR) and, only in the postmenopause, to an increase in circulating estradiol. Patients with breast cancer showed enhanced blood plasma concentrations of progesterone and estradiol, and enhanced tissue levels of ER and PGR associated with increased leptin levels. The data from the present study indicate that, in gynaecological and breast cancers, leptin is related to hormonal status but not to cachexia. We suggest that leptin stimulates the production of sexual hormones, important risk factors for these tumours, and we propose leptin as a novel prognostic marker.

    Topics: Adipocytes; Biomarkers, Tumor; Body Mass Index; Body Weight; Breast Neoplasms; Cachexia; Case-Control Studies; Female; Humans; Leptin; Neoplastic Cells, Circulating; Ovarian Neoplasms; Receptors, Estrogen; Receptors, Progesterone; Uterine Neoplasms

2004
Leptin expression in breast nipple aspirate fluid (NAF) and serum is influenced by body mass index (BMI) but not by the presence of breast cancer.
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2004, Volume: 36, Issue:5

    While obesity is a known risk factor for postmenopausal breast cancer, the molecular mechanisms involved are unclear. Systemic levels of leptin, the product of the ob (obesity) gene, are increased in obese individuals (body mass index, BMI, over 25) and are higher in women than men. Leptin has been found to stimulate the growth of breast cancer cells in vitro. Our goal was to determine whether leptin was 1) present in nipple aspirate fluid (NAF), and 2) whether NAF leptin levels were associated with a) levels in serum, b) obesity, and c) breast cancer. We collected and evaluated NAF specimens from 83 subjects and serum specimens from 49 subjects. NAF leptin was detectable in 16/41 (39 %) of premenopausal and 21/42 (50 %) postmenopausal subjects. NAF leptin was significantly lower (p = 0.042) in premenopausal than postmenopausal women with a BMI < 25, but not in those with a higher BMI. NAF leptin was significantly associated with BMI in premenopausal (p = 0.011) but not in postmenopausal women. Serum leptin was associated with BMI in both premenopausal and postmenopausal women (p = 0.0001 for both). NAF and serum leptin were associated in premenopausal (p = 0.02) but not postmenopausal women. Neither NAF nor serum leptin was associated with premenopausal or postmenopausal breast cancer. Our findings include that 1) leptin is present in the breast and detectable in a subset of NAF samples, 2) NAF leptin in premenopausal but not postmenopausal women parallels serum leptin levels, and 3) neither NAF nor serum levels of leptin were associated with premenopausal or postmenopausal breast cancer.

    Topics: Adult; Aged; Aged, 80 and over; Biopsy, Needle; Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Middle Aged; Nipples; Postmenopause; Premenopause

2004
[Diurnal rhythm of serum leptin in patients with solid tumors].
    Vnitrni lekarstvi, 2004, Volume: 50, Issue:4

    Leptin is a protein produced by fat tissue. It has many regulatory effects in the area of energetic metabolism, immunity and haematopoiesis. Its role in tumour diseases especially in states with cachexia is studied. Its physiological diurnal rhythm is very well known. There is lack of information about diurnal rhythm of leptin in tumour diseases except some endocrine tumours. In this study 10 patients with breast and colorectal cancer without marks of kachexia and mostly without pre-existing chemotherapy were examined. The diurnal rhythm of leptin was preserved in cancer patients (morning minimum 10.5 +/- 4.2 ng/ml and nocturnal maximum 17.9 +/- 10.1 ng/ml). The difference between males and females (p < 0.01) and correlation of concentrations of leptin with BMI (r = 0.61, p < 0.001) were preserved too. Basal concentrations of leptin were not different from values of healthy blood donors (10.2 +/- 4.3 ng/ml). Maybe preservation of diurnal rhythm of leptin can be important in planning of cytostatic and immunomodulatory therapy in future.

    Topics: Breast Neoplasms; Circadian Rhythm; Colorectal Neoplasms; Female; Humans; Leptin; Male; Middle Aged

2004
Enhanced expression of leptin and leptin receptor (OB-R) in human breast cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2004, Jul-01, Volume: 10, Issue:13

    To evaluate leptin and leptin receptor (OB-R) expression in human breast cancer and determine whether it could be effective for the prevention and treatment of breast cancer.. Immunohistochemical staining using specific antibodies was used to evaluate the protein expression of leptin and OB-R in 76 invasive ductal carcinomas and 32 samples of corresponding normal mammary gland, and the relationship between the expression of OB-R and leptin and clinicopathological features was analyzed.. Normal mammary epithelial cells did not express a significant level of Ob-R, whereas carcinoma cells showed positive staining for OB-R in 63 (83%) cases. Both normal epithelial cells and carcinoma cells expressed a significant level of leptin. However, overexpression of leptin, as determined by staining intensity, was observed in 70 cancers (92%) but in no normal epithelium. The expression of OB-R showed a significant correlation with the level of leptin expression. Interestingly, distant metastasis was detected in 21 (34%) of 61 OB-R-positive tumors with leptin overexpression, but in none of the 15 tumors that lacked OB-R expression or leptin overexpression (P < 0.05). Consequently, patients with the former tumors showed significantly lower survival than those with the latter.. Leptin may have a promoting effect on the carcinogenesis and metastasis of breast cancer, possibly in an autocrine manner. Functional inhibition of leptin may be effective for the prevention and treatment of breast cancer.

    Topics: Adipose Tissue; Adult; Aged; Breast; Breast Neoplasms; Carcinoma, Ductal; Cells, Cultured; Epithelium; Female; Humans; Immunohistochemistry; Leptin; Male; Mammary Glands, Human; Middle Aged; Neoplasm Metastasis; Receptors, Cell Surface; Receptors, Leptin; Risk; Time Factors

2004
Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin.
    Cancer research, 2004, Aug-15, Volume: 64, Issue:16

    Obesity is a risk factor for breast cancer in postmenopausal women. Leptin, an adipocyte-derived cytokine, elicits proliferative effects in some cell types and potentially stimulates the growth of mammary epithelium. Here we show that leptin induced time- and dose-dependent signal transducer and activator of transcription 3 (STAT3) phosphorylation and extracellular signal-regulated kinase (ERK) 1/2 kinase activation in breast carcinoma cells. Blocking STAT3 phosphorylation with a specific inhibitor, AG490, abolished leptin-induced proliferation of MCF-7 cells, whereas blocking ERK1/2 activation by a specific ERK1/2 kinase inhibitor, U0126, did not result in any significant changes in leptin-induced cell proliferation. Our experiments also showed that one member of the p160 family of steroid receptor coactivators, steroid receptor coactivator (SRC)-1, but not glucocorticoid receptor interacting protein 1 (GRIP1) or amplified in breast cancer 1 (AIB1), also functioned in gene transactivation in response to leptin treatment. Glutathione S-transferase pull-down experiments showed that SRC-1 physically interacted with the activation domain of STAT3 and that chromatin immunoprecipitation experiments detected the occupancy of SRC-1, but not GRIP1 or AIB1, on the promoter of STAT3 target genes. Our experiments collectively showed that SRC-1 is involved in STAT3 signaling pathway that is implicated in leptin-stimulated cell growth.

    Topics: Breast Neoplasms; Carrier Proteins; Cell Division; Cell Line, Tumor; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, myc; Histone Acetyltransferases; Humans; Leptin; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Nuclear Receptor Coactivator 1; Nuclear Receptor Coactivator 3; Promoter Regions, Genetic; Receptors, AMPA; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Transcription Factors; Transcriptional Activation

2004
Leptin interferes with the effects of the antiestrogen ICI 182,780 in MCF-7 breast cancer cells.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2004, Oct-01, Volume: 10, Issue:19

    Obesity is a risk factor for breast cancer development in postmenopausal women and correlates with shorter disease-free and overall survival in breast cancer patients, regardless of menopausal status. Adipose tissue is a major source of leptin, a cytokine regulating energy balance and controlling different processes in peripheral tissues, including breast cancer cell growth. Here, we investigated whether leptin can counteract antitumorigenic activities of the antiestrogen ICI 182,780 in breast cancer cells.. Mitogenic response to leptin and the effects of leptin on ICI 182,780-dependent growth inhibition were studied in MCF-7 estrogen receptor alpha-positive breast cancer cells. The expression of leptin receptor and the activation of signaling pathways were studied by Western immunoblotting. The interference of leptin with ICI 182,780-induced estrogen receptor alpha degradation was probed by Western immunoblotting, fluorescence microscopy, and pulse-chase experiments. Leptin effects on estrogen receptor alpha-dependent transcription in the presence and absence of ICI 182,780 were studied by luciferase reporter assays and chromatin immunoprecipitation.. MCF-7 cells were found to express the leptin receptor and respond to leptin with cell growth and activation the signal transducers and activators of transcription 3, extracellular signal-regulated kinase-1/2, and Akt/GSK3/pRb pathways. The exposure of cells to 10 nmol/L ICI 182,780 blocked cell proliferation, induced rapid estrogen receptor alpha degradation, inhibited nuclear estrogen receptor alpha expression, and reduced estrogen receptor alpha-dependent transcription from estrogen response element-containing promoters. All of these effects of ICI 182,780 were significantly attenuated by simultaneous treatment of cells with 100 ng/mL leptin.. Leptin interferes with the effects of ICI 182,780 on estrogen receptor alpha in breast cancer cells. Thus, high leptin levels in obese breast cancer patients might contribute to the development of antiestrogen resistance.

    Topics: Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Division; Cell Line, Tumor; Cell Proliferation; Chromatin Immunoprecipitation; DNA-Binding Proteins; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogens; Female; Fulvestrant; Gene Expression; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Leptin; Luciferases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface; Receptors, Leptin; Recombinant Fusion Proteins; Response Elements; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Transcription, Genetic; Ubiquitin

2004
Plasma leptin and breast cancer risk: a prospective study in northern Sweden.
    Breast cancer research and treatment, 2004, Volume: 86, Issue:3

    Obesity is associated with risk of breast cancer after menopause. Circulating levels of leptin are high in obesity and leptin stimulates growth of breast cancer cells.. In a case-control study nested within the Northern Sweden Health and Disease Cohort, we measured leptin levels in prediagnostic plasma from 149 postmenopausal women who were diagnosed with breast cancer at a mean time 1.7 years (SD 2.0) after recruitment and among 258 control subjects.. No significant association between plasma levels of leptin and breast cancer risk was observed. Odds ratios (ORs) of breast cancer with increasing levels of leptin were 1.00 [referent], 1.01 [95% CI = 0.58-1.84], 0.65 [0.36-1.18], and 0.94 [0.53-1.67], and (p(for trend) = 0.54). Adjustment for smoking, body mass index, and plasma insulin did not affect risk estimates.. These data do not support the hypothesis that plasma leptin is a risk factor for breast cancer.

    Topics: Aged; Breast Neoplasms; Case-Control Studies; Female; Humans; Leptin; Middle Aged; Odds Ratio; Prospective Studies; Risk Factors; Sweden

2004
Serum leptin levels are associated with tamoxifen-induced hepatic steatosis.
    Current medical research and opinion, 2003, Volume: 19, Issue:1

    Tamoxifen, used in breast cancer treatment, may induce hepatic steatosis. It has been suggested that leptin, which has a relationship with body fat stores, may be involved in the pathogenesis of hepatic steatosis. In this study, we compared serum leptin levels in tamoxifen-treated patients with and without hepatic steatosis.. Thirty-four women with breast cancer receiving tamoxifen were included in the study. Serum samples were obtained from the patients before and 3 months after tamoxifen therapy.. Increased hepatic steatosis was detected in 15 of 34 (44%) patients after 3 months of tamoxifen therapy. Serum leptin levels were found to be significantly elevated in patients with increased hepatic steatosis (37.3 +/- 17.7 to 50.5 +/- 22.4 ng/ml, p = 0.023) compared to (48.2 +/- 20.2 to 42.6 +/- 14.9 ng/ml, p > 0.05) after tamoxifen treatment.. Leptin may play a role in tamoxifen-induced hepatic steatosis. The exact mechanism involved should be investigated in further studies.

    Topics: Adipose Tissue; Adult; Aged; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cholesterol; Fatty Liver; Female; Humans; Leptin; Liver Function Tests; Middle Aged; Tamoxifen; Triglycerides

2003
Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer.
    Neoplasma, 2003, Volume: 50, Issue:1

    Angiogenesis plays an important role in tumor growth and metastasis in solid tumors. VEGF is an important regulator of tumor angiogenesis. Both leptin and prolactin have also been suggested to have roles in the regulation of angiogenic process. In our study, we measured serum leptin, prolactin and VEGF levels in 30 metastatic, 55 non-metastatic breast cancer patients and 25 control subjects. Serum leptin levels were found to be similar in non-metastatic (38.1+/-19.5 ng/ml), metastatic patients (39.6+/-16.3 ng/ml) and control subjects (35.6+/-13.9 ng/ml) (p>0.05). There was no statistically significant difference between patients with visceral metastasis (44.0+/-16.8 ng/ml) and patients with bone metastasis (35.2+/-15.0 ng/ml) (p>0.05). Serum prolactin levels were found to be similar in non-metastatic (12.2+/-10.7 ng/ml), metastatic patients (11.6+/-8.2 ng/ml) and control subjects (12.3+/-8.1 ng/ml), (p>0.05). Moreover, serum prolactin levels were not different in patients with visceral (11.4+/-8.8 ng/ml) and bone metastasis (11.8+/-8.0 ng/ml), (p>0.05). Metastatic patients had higher serum VEGF levels (249.8+/-154.9 pg/ml), when compared to the non-metastatic patients (138.7+/-59.3 pg/ml) and control subjects (108.4+/-47.7 pg/ml), (p<0.05). There was no difference in serum VEGF levels in non-metastatic patients and control subjects (p>0.05). Patients with visceral metastasis (337.0+/-168.0 pg/ml) had higher serum VEGF levels, when compared to patients with bone metastasis (162.6+71.8 pg/ml), (p<0.05). Serum VEGF activity may be used to evaluate angiogenic and metastatic activity in breast cancer patients. However, serum leptin and prolactin levels does not seem to be related with angiogenic activity and metastasis in breast cancer patients.

    Topics: Adult; Breast Neoplasms; Carcinoembryonic Antigen; Endothelial Growth Factors; Female; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Lymphokines; Mucin-1; Neoplasm Metastasis; Neovascularization, Pathologic; Prolactin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

2003
A multigene test for the risk of sporadic breast carcinoma.
    Cancer, 2003, May-01, Volume: 97, Issue:9

    Although the identification of the BRCA1 and BRCA2 genes have been of great interest, these genes account for less than 5% of all breast carcinoma cases. The remaining cases are sporadic. Reanalysis of a large twin study suggested that genetic factors may play a significant role in sporadic breast and other carcinomas. Sporadic breast carcinoma is polygenically inherited. Multiple genes are likely to have an additive effect, each gene accounting for a fraction of the variance. One factor that may have an impact on the development of hormonally responsive breast tumors is the duration of exposure of the breast to estrogen. Therefore, one of the demographic risk factors for breast carcinoma is an early age of onset of menarche. The current study was based on the hypothesis that genes that play a role in demographic risk factors may be breast carcinoma risk genes in their own right. The authors hypothesized that six genes relevant to the timing of the onset of menarche and related risk factors might be candidate genes for breast carcinoma. These were the leptin gene (LEP), the leptin receptor gene (LEPR), the catechol-0-methyltransferase gene (COMT), the dopamine D(2) receptor gene (DRD2), the estrogen 1 receptor gene (ESR1), and the androgen receptor gene (AR).. The authors examined 67 women with postmenopausal sporadic breast carcinoma and 145 gender and race-matched controls.. Five of these genes accounted for a significant percent of the variance (r(2)) of breast carcinoma. The following r(2) and P values were calculated: LEP: 0.073, P < or = 0.0001; LEPR: 0.064, P < or = 0.0002; COMT: 0.073, P < or = 0.0001; AR: 0.040, P < or = 0.0035; and DRD2: 0.018, P < or = 0.05. When evaluated in a multivariate regression analysis, they accounted collectively for 24% of the variance of breast carcinoma (P < or = 0.0001). These genes accounted for 40% of the variance (P < or = 0.00001) in a subset of age-matched cases. Individual gene scores were added to form a breast carcinoma risk score (BCRS) that ranged from 0 to 17. When the BCRS was evaluated in a receiver operator characteristic plot, the area under the curve was 0.80 for the full set and 0.869 for the age-matched set. The relative breast carcinoma risk for the different BCRS scores ranged from 0.10 to 11.9.. These results demonstrate a potentially powerful method of evaluating the additive effect of multiple breast carcinoma risk genes to form a potentially clinically useful assessment of women's risk for sporadic breast carcinoma.

    Topics: Adult; Age Distribution; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Case-Control Studies; Catechol O-Methyltransferase; Female; Genetic Predisposition to Disease; Genotype; Humans; Leptin; Middle Aged; Neoplasm Proteins; Polymorphism, Genetic; Receptors, Androgen; Receptors, Cell Surface; Receptors, Dopamine D2; Receptors, Estrogen; Receptors, Leptin; Risk Factors; ROC Curve; Sensitivity and Specificity

2003
Leptin enhances, via AP-1, expression of aromatase in the MCF-7 cell line.
    The Journal of biological chemistry, 2003, Aug-01, Volume: 278, Issue:31

    Leptin, a product of adipocytes, is involved in the regulation of body weight and results strongly correlated to body fat content. An excess of fat mass represents a breast cancer risk factor particularly in postmenopausal women, where estrogen production by adipose tissue through its own aromatase activity stimulates tumor progression. Leptin stimulates estrogen production through the increase of aromatase expression and activity in human luteinized granulosa cells and adipose stromal cells. In the present study, we have examined the possible link that exists between leptin and breast cancer, focusing our attention on the direct effect of leptin on aromatase activity, which may enhance estrogen production and induce tumor cell growth stimulation. We have shown that leptin enhances aromatase mRNA expression, aromatase content, and its enzymatic activity in MCF-7. Aromatase expression appears to be regulated by tissue-specific promoter. It has been demonstrated that promoters II and 1.3 are the major promoters that drive aromatase expression in MCF-7. Transient transfection experiments using vector containing human aromatase promoters II and 1.3 sequence fused with luciferase reporter gene demonstrated that leptin is able to activate this promoter. In the presence of either mitogen-activated protein kinase inhibitor PD 98059 or ERK2 dominant negative as well as in the presence of STAT3 dominant negative, the stimulatory effects of leptin on aromatase promoter, enzymatic activity, and aromatase protein content were inhibited. Functional studies of mutagenesis and electrophoretic mobility shift assay revealed that the AP-1 motif is important in determining the up-regulatory effects induced by leptin on aromatase expression in MCF-7.

    Topics: Androstenedione; Aromatase; Breast Neoplasms; Cell Division; DNA; DNA-Binding Proteins; Estradiol; Estrogen Receptor alpha; Gene Expression Regulation, Enzymologic; Humans; Leptin; Luciferases; Mitogen-Activated Protein Kinases; Promoter Regions, Genetic; Receptors, Estrogen; Recombinant Fusion Proteins; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Transcription Factor AP-1; Transfection; Tumor Cells, Cultured

2003
Re: Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development.
    Journal of the National Cancer Institute, 2003, Aug-06, Volume: 95, Issue:15

    Topics: Breast; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Recombinant Proteins; Transcription, Genetic; Tumor Cells, Cultured

2003
Differential effects of leptin on cancer in vitro.
    The Journal of surgical research, 2003, Volume: 113, Issue:1

    Leptin, a protein produced by adipocytes, is an important signaling molecule in energy regulation and food intake. Many obese patients have leptin resistance associated with increased circulating leptin. Leptin receptor activation downregulates many regulatory genes, including STAT-3 and PAP 1. Certain cancers are associated with obesity, including breast, prostate, and colon. Recent studies have shown that leptin stimulates proliferation of human colon cancer in vitro. We hypothesized that leptin would have stimulatory effects on other human cancers.. Human cancer cell lines from esophagus (KYSE410 and 150), breast (ZR75-1 and MCF-7), prostate (DU145 and PC-3), and pancreas (PANC-1, Mia-PaCa) were cultured using standard techniques. Leptin (0.4 ng/ml and 4.0 ng/ml) was added for 24 h and 48 h. Cell growth was determined by MTT assay. Statistical analysis was performed using analysis of variance.. Cancer cell lines demonstrated dose- and time-related responses to treatment. Leptin caused growth potentiation in breast, esophagus, and prostate cancer (P < 0.05). However, in both Mia-PaCa and PANC-1 pancreatic cancer cells, leptin inhibited growth (P < 0.05). This inhibitory effect peaked in PANC-1 at 48 h (78%).. We have shown for the first time that human cancer cells exhibit differential responses to treatment with leptin, depending upon organ of derivation. Both leptin and leptin antagonism have potential efficacy in cancer therapy, based on cellular origin. Further studies are warranted and ongoing.

    Topics: Breast Neoplasms; Cell Division; Esophageal Neoplasms; Female; Humans; Leptin; Male; Neoplastic Processes; Pancreatic Neoplasms; Pancreatitis-Associated Proteins; Peptide Hormones; Prostatic Neoplasms; Tumor Cells, Cultured

2003
Leptin and high glucose stimulate cell proliferation in MCF-7 human breast cancer cells: reciprocal involvement of PKC-alpha and PPAR expression.
    Biochimica et biophysica acta, 2002, Oct-21, Volume: 1592, Issue:2

    Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-alpha, PPARgamma, and PPARalpha protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-alpha, PPARalpha, and PPARgamma.

    Topics: Breast Neoplasms; CDC2-CDC28 Kinases; Cell Cycle; Cell Division; Cyclin D1; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; DNA; Dose-Response Relationship, Drug; Drug Resistance; Glucose; Humans; Isoenzymes; Leptin; Protein Kinase C; Protein Kinase C-alpha; Protein Serine-Threonine Kinases; Receptors, Cytoplasmic and Nuclear; Thymidine; Transcription Factors; Tumor Cells, Cultured; Up-Regulation

2002
Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development.
    Journal of the National Cancer Institute, 2002, Nov-20, Volume: 94, Issue:22

    Obesity is a risk factor for breast cancer in postmenopausal women. As body weight and fat mass increase, circulating leptin increases. Leptin is an adipocyte-derived cytokine that acts through the long form of its receptor, termed OB-Rb. To investigate whether leptin is associated with breast cancer, we determined the expression of OB-Rb in human breast epithelial HBL100 cells and human breast carcinoma-derived T-47D cells, determined whether leptin influenced the proliferation of these cells, and evaluated the structure of mammary tissue in genetically obese leptin-deficient Lep(ob)Lep(ob) and leptin receptor-deficient Lepr(db)Lepr(db) mice.. Cell numbers and cell colony formation by HBL100 and T-47D cells were determined by anchorage-dependent and anchorage-independent growth assays. OB-Rb expression was examined by reverse transcription-polymerase chain reaction and immunoblot analyses. Expression of leptin signaling pathway components was evaluated with immunoblot and electrophoretic mobility shift assays. Mammary gland development in lean and obese mice was investigated in whole-mount studies. All statistical tests were two-sided.. Leptin enhanced anchorage-dependent proliferation by 138% (95% confidence interval [CI] = 108% to 169%) in T-47D cells and 50% (95% CI = 38% to 60%) in HBL100 cells. In both cell lines, OB-Rb was expressed, and leptin increased the expression of phosphorylated signal transducers and activators of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase (ERK), and transcript activator protein 1 (AP-1). However, leptin increased anchorage-independent cell growth only in the breast cancer cell line (by 81% [95% CI = 62% to 101%] compared with untreated cells). Obese Lep(ob)Lep(ob) and Lepr(db)Lepr(db) mice had minimal epithelial development in the mature mammary gland compared with their lean counterparts.. Leptin appears to be able to control the proliferation of both normal and malignant breast epithelial cells. Consequently, the leptin pathway should be further studied as a target for interventions to treat or prevent breast cancer.

    Topics: Animals; Blotting, Western; Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Cell Line; DNA-Binding Proteins; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Mice; Mice, Obese; Obesity; Phosphorylation; Protein Tyrosine Phosphatases; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured

2002
Leptin mediates a proliferative response in human MCF7 breast cancer cells.
    Biochemical and biophysical research communications, 2002, Apr-26, Volume: 293, Issue:1

    Obesity is a risk factor of breast cancers. As leptin, a hormone mainly secreted by white adipocytes, elicits proliferative effects in some cell types, we tested the hypothesis that leptin could influence human breast cancer MCF-7 cell growth. Here we show that MCF-7 cells express leptin receptors and respond to human recombinant leptin by STAT3 and p42/p44 MAPkinase activations and by increased proliferation. These findings suggest that leptin could act in vivo as a paracrine/endocrine growth factor towards mammary epithelial cells thus contributing to explain why obesity is a risk factor of developing breast cancers.

    Topics: Acute-Phase Proteins; Adipocytes; Breast Neoplasms; Cell Division; DNA-Binding Proteins; DNA, Neoplasm; Female; Humans; Leptin; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Obesity; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; STAT3 Transcription Factor; Thymidine; Trans-Activators; Tumor Cells, Cultured

2002
Effects of estrogen on leptin gene promoter activation in MCF-7 breast cancer and JEG-3 choriocarcinoma cells: selective regulation via estrogen receptors alpha and beta.
    Molecular and cellular endocrinology, 2001, May-15, Volume: 176, Issue:1-2

    Leptin is a potential regulator of conceptus development. We have previously suggested that in primate pregnancy, leptin biosynthesis is regulated by estrogen in a tissue-specific manner. Therefore, the objective of the current study was to determine the mechanism of estrogen action on LEP promoter activation in divergent cell types. The effects of estrogen were investigated in estrogen receptor (ER)-positive MCF-7 breast cancer cells and in ER-negative JEG-3 choriocarcinoma cells. Cells were transfected with a leptin-luciferase or an estrogen responsive element (ERE)-luciferase reporter construct, in conjunction with ERalpha, ERbeta, or empty vector expression plasmids. Cells were treated with estradiol and/or the specific estrogen antagonists, ICI-182,780 or 4-hydroxytamoxifen. In MCF-7 cells, estradiol stimulated (P<0.05) ERE-luciferase activity and was inhibited by ICI-182,780, but did not stimulate leptin-luciferase activity. However, leptin-luciferase was stimulated by estradiol (P<0.05) and inhibited by antiestrogens in JEG-3 cells that were co-transfected with ERalpha. Both antiestrogens stimulated leptin-luciferase activity (P<0.05) in JEG-3 cells co-transfected with ERbeta. Results suggested that LEP promoter activation may depend upon co-activators present in leptin-producing cells and may be inhibited by repressors present in non-leptin producing cells. Divergent effects of estrogen may be owed to differences in the type of ER (alpha or beta) expressed in target tissues.

    Topics: Breast Neoplasms; Choriocarcinoma; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fulvestrant; Genes, Reporter; Humans; Leptin; Promoter Regions, Genetic; Receptors, Estrogen; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcriptional Activation; Transfection; Tumor Cells, Cultured

2001
Effects of tamoxifen on the serum leptin level in patients with breast cancer.
    Japanese journal of clinical oncology, 2001, Volume: 31, Issue:9

    Leptin is a peptide hormone that has a role in the regulation of body weight and has effects on metabolic, neuroendocrine, reproductive and hematopoietic systems. Breast cancer has also been associated with obesity and reproductive hormones, especially estradiol. Only a few studies have investigated the relation between plasma leptin and risk of breast cancer and only one study evaluated the effect of tamoxifen on leptin levels in patients with breast cancer.. We investigated serum leptin levels in gender-, body mass index (BMI)- and age-matched breast cancer patients and healthy individuals (58 of each).. Serum leptin levels were measured by radioimmunoassay (Human Leptin RIA Kit). Serum leptin levels in the breast cancer patients were significantly higher than those in the control group (27.00 versus 17.65 ng/ml, p = 0.019). There were no differences with respect to BMI and age between control and breast cancer patients. There were no significant differences in BMI and leptin levels between pre- and postmenopausal patients (27.00 +/- 1.39 and 27.19 +/- 0.81 kg/m(2), 26.81 +/- 6.25 and 27.06 +/- 2.98 ng/ml) (p > 0.05). We found no difference in serum leptin level between early and late stages of patients (22.38 versus 31.30 ng/ml, p = 0.086). However, the serum leptin level in patients using tamoxifen was significantly higher than that of patients not using tamoxifen (32.71 and 19.39 ng/ml, respectively p = 0.009). There was no correlation between CA 15-3 and leptin level (r = 0.069, p = 0.610).. High serum leptin levels seen in breast cancer patients are not related to stage of the disease or to cancer itself but may be associated with the use of tamoxifen.

    Topics: Adult; Aged; Antineoplastic Agents, Hormonal; Body Mass Index; Breast Neoplasms; Female; Humans; Leptin; Middle Aged; Tamoxifen

2001
Leptin expression in colorectal and breast cancer patients.
    International journal of molecular medicine, 2000, Volume: 5, Issue:4

    Leptin is a hormone which controls fat metabolism. Leptin plasma levels and adipose tissue mRNA expression were measured in cancer patients. Plasma levels were correlated with TNM staging, cachexia parameters, tumour markers and hormones. Breast and colorectal cancer patients showed blood plasma levels of insulin, TNF-alpha and tumour markers higher than controls. Breast cancer patients, but not colorectal cancer patients, had plasma levels and adipose tissue expression of leptin significantly higher than controls associated with elevated values of estrogen- and progesterone-receptors. These data suggest the possible use of leptin as a clinical marker.

    Topics: Adenocarcinoma; Adipose Tissue; Adult; Aged; Biomarkers, Tumor; Blotting, Northern; Breast Neoplasms; Colorectal Neoplasms; Female; Gene Expression; Humans; In Situ Hybridization; Leptin; Male; Middle Aged; Neoplasm Staging; Radioimmunoassay; RNA, Messenger; Tumor Necrosis Factor-alpha

2000
Leptin and insulin growth factor I in relation to breast cancer (Greece).
    Cancer causes & control : CCC, 2000, Volume: 11, Issue:5

    Because both breast cancer and the hormone leptin are associated with obesity and reproductive phenomena in women, we have examined whether there is a relationship between leptin and breast cancer among premenopausal and postmenopausal women. We have also evaluated in this dataset the association of IGF-I with breast cancer.. Seventy-five cases, diagnosed during mammographic screening, with incident breast cancer were matched for age and type of permanent residence with seventy-five controls from those screened negative in the same study base.. There was no evidence for an association between IGF-I and either premenopausal or postmenopausal breast cancer risk or between leptin and postmenopausal breast cancer. Among premenopausal women, however, there was a strong and statistically significant inverse association of leptin with breast cancer.. We did not confirm the positive association, reported from other investigations, of IGF-I with premenopausal breast cancer risk. We have found evidence, however, that leptin may be inversely related to breast cancer risk among premenopausal women. The latter finding is not biologically implausible and deserves to be examined in additional datasets.

    Topics: Adult; Aged; Breast Neoplasms; Case-Control Studies; Female; Greece; Humans; Incidence; Insulin-Like Growth Factor I; Leptin; Menopause; Middle Aged

2000
Leptin in relation to carcinoma in situ of the breast: a study of pre-menopausal cases and controls.
    International journal of cancer, 1999, Feb-09, Volume: 80, Issue:4

    Leptin reflects the amount of energy stores, regulates energy balance and is associated with circulating levels of reproductive hormones and insulin-like growth factor-I (IGF-I). Breast cancer has also been associated with obesity, reproductive hormones and circulating IGF-I levels. To determine whether leptin is involved in the etiology of breast cancer, we compared serum leptin levels in 83 cases of pre-menopausal carcinoma in situ of the breast and 69 healthy controls recruited in Massachusetts. Serum leptin levels were 13.69 + 1.3 ng/ml in cases and 16.03 + 1.7 ng/ml in controls. Data were also analyzed using multiple logistic regression with adjustment for known risk factors for the development of breast cancer as well as anthropometric, demographic and hormonal variables, including estradiol, prolactin, IGF-I and IGF-binding protein-3. Odds ratios were 1.75 (95% CI, 0.73-4.21) for the second control-defined tertile and 1.54 (0.46-5.16) for the third control-defined tertile relative to the first. Thus, leptin does not appear to increase the risk of pre-menopausal breast cancer in situ substantially.

    Topics: Adult; Biomarkers; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Case-Control Studies; Estradiol; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Middle Aged; Premenopause; Prolactin; Proteins

1999
Presence of leptin in breast cell lines and breast tumors.
    Biochemical and biophysical research communications, 1999, Jun-16, Volume: 259, Issue:3

    Leptin is the product of the ob gene, reported to be secreted exclusively from adipocytes and thought to control satiety by providing information to the central nervous system. However, the function of leptin appears to be more complex because multiple studies demonstrate its role in hematopoiesis, reproduction, and immunity. In addition, several nonadipose sources of leptin have been reported. The purpose of this study was to examine several breast cancer cell lines and ductal carcinomas of the breast for expression of leptin messenger RNA (mRNA) and protein. For tumor studies, specimens were preassayed for contaminating adipose tissue. Northern blot analyses demonstrated leptin mRNA in several breast cancer cell lines (MCF-7, T47D, and MDA-MB-231), a normal breast epithelial cell line (MCF10A), and four breast tumors. Leptin protein was identified in T47D breast cancer cells by indirect immunofluorescent staining and in samples of the same breast tumors used for Northern studies by enzyme-linked immunosorbent assays (ELISA). This preliminary study suggests that leptin is expressed in malignant epithelial cells of the breast. Further investigation is needed to determine whether this protein plays a role in breast carcinogenesis.

    Topics: Adipose Tissue; Breast; Breast Neoplasms; Cell Line; Fluorescent Antibody Technique; Humans; Leptin; Proteins; RNA, Messenger; Tumor Cells, Cultured

1999