Phytoestrogens for breast cancer-Soy Phytoestrogens and Breast Cancer: An Enduring Dilemma - The ASCO Post

Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed. Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors p21 and p27 and the tumour suppressor gene p Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes.

Phytoestrogens for breast cancer

The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? This sulfation may further influence the bioavailability of endogenous oestrogens and alter the ratio of active oestrogens and inactive oestrogen sulfates. White, Asian, and Hispanic women are Acta Naturae7 3— The link between breast cancer and phytoestrogens arose from the early epidemiologal evidence showing that the incidence of breast cancer is lower in Asian populations who consume high dietary concentrations of soy products which have a high isoflavonone content[ 12 ]. What are the signs of ketosis? Acute and chronic effects of genistein, tyrphostin and lavendustin A on steroid synthesis in luteinized Phytoestrogens for breast cancer Powerpuff girls anime porno cells.

Free busty holly. Sign Up Our FREE Monthly E-Journal

Breast Cancer Res Treat. Similarly, several studies have demonstrated that rats exposed to genistein early in life have a decreased incidence of DMBA-induced mammary tumors in adulthood Fritz et al. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells. Resveratrol, Phytoestrogenz polyphenolic compound found in grapes and Phytoestrogens for breast cancer, is an agonist for the estrogen receptor. Sign In or Create an Account. Cyp19 catalyzes the conversion of androstenedione and testosterone to estrone E Model search sean john and E 2Phytoestrogens for breast cancer Thompson and Siiteri Ecologic observations indicate that the incidence of breast cancer is much lower in Asian women, who consume significantly higher amounts of phytoestrogens than Western women Adlercreutz The specific role of isoflavones on Phytoestrogens for breast cancer metabolism in pre-menopausal women. A randomized isoflavone intervention among premenopausal women. Researchers have shown that flaxseed sprouts can increase apoptosis programmed cell death. Although their medical importance has been less extensively studied, lignans occur in higher concentrations in US fod European diets than do isoflavones.

Phytoestrogens are plant nutrients found in several different types of food such as soy products, grains, beans, and some fruits and vegetables.

  • Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer.
  • Phytoestrogens are plant nutrients found in several different types of food such as soy products, grains, beans, and some fruits and vegetables.
  • Phytoestrogens, a group of food-based compounds commonly associated with soy products and available in oral supplements, are connected with a wide range of health benefits, including lowered risks of breast cancer, heart disease, and symptoms of menopause.

By Barrie R. The impact of soy consumption on breast cancer diagnosis and outcome has remained of concern to clinicians and researchers for the past 20 years.

This is a major issue of confusion for patients, who are exposed to conflicting media reports and marketed soy products with poorly supported health claims. Inconsistency in research findings, noncomparable study designs, and a dearth of clinical trials that assess the effect of soy on breast cancer outcome in humans have precluded the development of rigorous evidence-based guidelines to date.

In this overview, we aim to summarize relevant findings and existing recommendations that may be useful to clinicians. Soy Glycine max is a major source of isoflavones, particularly genistein and daidzein.

These compounds are structurally similar to endogenous estrogen, and may act as selective estrogen receptor modulators with the ability to stimulate or inhibit depending on factors such as isoflavone concentration and the distribution of estrogen receptor types. Isoflavones also may modulate breast carcinogenesis via nonhormonal pathways.

Much of this research used isolated genistein. However, data from at least one animal study in which soy isoflavones promoted tumor growth suggests that this effect is not seen when whole soy is consumed instead of isoflavones alone. To reduce the risk of breast cancer, epidemiologic evidence generally describes an inverse relationship between soy consumption and breast cancer diagnoses, although the observed degree of protective benefit varies depending on the patients studied.

Both dosage and timing of exposure to soy isoflavones appear relevant to their potential chemopreventive effect. Two recent meta-analyses 2,3 found soy intake to be significantly associated with reduced risk of breast cancer in Asian but not Western populations, which may be explained by both higher soy intake among Asians and their tendency to consume soy from an early age.

Several epidemiologic studies in fact suggest that diets rich in soy early in life and through puberty are associated with a decreased risk of breast cancer—and that introducing isoflavones into the diets of adult women may not have much impact on their cancer risk. Three large epidemiologic studies published over the past few years, two in U. The ACS position gained further support just 1 month after its release from an even larger study of 9, U.

Despite some contradictory evidence in lab studies and animal models, a growing body of epidemiologic evidence suggests that soy food is safe to consume at moderate levels, and that clinicians need not advise against soy foods for breast cancer patients or survivors. Patients should avoid soy supplements, however, as these often provide very high doses of isoflavones and have not been well studied.

Disclosure: Dr. Cassileth and Mr. Yarett reported no potential conflicts of interest. J Natl Cancer Inst , Dong JY, Qin LQ: Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. Breast Cancer Res Treat , Br J Cancer , J Nutr SS, Carcinogenesis , Nutr Rev , Cancer , Nagata C: Factors to consider in the association between soy isoflavone intake and breast cancer risk.

J Epidemiol , Messina M, Hilakivi-Clarke L: Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer.

Nutr Cancer , Cancer Epidemiol Biomarkers Prev , JAMA , CA Cancer J Clin. April 26, early release online. Am J Clin Nutr , CA Cancer J Clin , Toggle navigation. Oct

However our study on human granulosa cells showed that low dose mixtures of three isoflavones in the nM range inhibited expression and activity of aromatase though a similar inhibition was only achieved with a single phytoestrogen at times the dosage[ 60 ]. Can Med Assoc J. Dietary intake of isoflavones and breast cancer risk by estrogen and progesterone receptor status. Many cosmetic and supplement companies advertise their products to increase breast size due to phytoestrogens, but use caution before you purchase these products. J Epidemiol. Dietary intakes of total and specific lignans are associated with clinical breast tumor characteristics. In foods phytoestrogens are present as mixtures and are usually found as biologically inactive glycoside conjugates containing glucose or carbohydrate moieties.

Phytoestrogens for breast cancer

Phytoestrogens for breast cancer. Phytoestrogens

The authors originally decided to calculate lignan intake on the basis of its bioactive forms enterolactone and enterodiol, which are referred to as mammalian lignans and are synthesized from plant lignans by gut microflora. Conversion factors were derived from an in vitro model for colonic fermentation. When the authors reanalyzed their data by using the absolute quantity of plant lignans matairesinol and secoisolariciresinol , the modest protective effect disappeared, and breast cancer risk increased slightly but nonsignificantly with increased lignan intake.

Following up on this inconsistency, they compared the intakes of plant lignans with estimates of bioavailable lignans and found that only one-third of the women in the cohort were assigned to comparable quartiles for both variables. Part of the problem was that food-composition data had not been calculated for several recently identified plant lignans 8 , which provide sizable quantities of bioactive lignans.

Plausible reasons for this discrepancy exist and reveal the complexity of this research. Urinary measures take into account individual variation in colonic metabolism and bioavailability, whereas dietary measures integrate exposure over a longer period of time. Finally, the study by Keinan-Boker et al was limited by the range of exposure in the population.

Neither lignan intake interquartile range: 0. Epidemiologic research on lignans and breast cancer is limited. Only 1 of the 3 published US studies that estimated dietary lignan intake found a protective effect Of the 2 breast cancer studies that measured circulating enterolactone, only 1, which was conducted in Finland, reported a persuasive inverse relation Of the 3 studies that assayed urinary lignans, only 2, which were carried out in Australia and China, reported a protective effect 12 , Explanations for these inconsistencies include the methodologic challenges mentioned above.

Women, especially those at high risk, want to know whether phytoestrogens decrease or increase breast cancer risk. Breast cancer survivors relying on tamoxifen to inhibit endogenous estrogen or on aromatase inhibitors to prevent its production question how phytoestrogens will interact with their treatment.

Perimenopausal and postmenopausal women searching for an alternative to synthetic hormone therapy wonder whether phytoestrogens might increase breast cancer risk and not substantially improve cardiovascular or bone health.

The relevant research is complicated, inconsistent, and inconclusive. At present, scientific research does not support increasing phytoestrogen intake among US women to Asian levels, nor does it suggest that the typical US phytoestrogen intake is problematic for healthy women. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.

Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Phytoestrogens and breast cancer Regina G Ziegler. Oxford Academic. Google Scholar. Cite Citation. Permissions Icon Permissions. Search ADS. De Kleijn. Cancer Statistics Estrogen receptor beta-selective transcriptional activity and recruitment of coregulators by phytoestrogens.

J Biol Chem. Comparison of isoflavones among dietary intake, plasma concentration and urinary excretion for accurate estimation of phytoestrogen intake. J Epidemiol. Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects. J Appl Toxicol. Role of human cytochrome P 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol.

Effects of genistein and structurally related phytoestrogens on cell cycle kinetics and apoptosis in MDA-MB human breast cancer cells. Oncol Rep. Estrogen receptor alpha and beta profiling in human breast cancer. Eur J Surg Oncol.

Suppression of 7,dimethylbenz a anthracene-induced mammary carcinogenesis in rats by resveratrol: role of nuclear factor-kappaB, cyclooxygenase 2, and matrix metalloprotease 9. Mol Pharmacol. Resveratrol inhibits benzo[ a ]pyrene-DNA adduct formation in human bronchial epithelial cells.

Br J Cancer. Critical role of oxidative stress in estrogen-induced carcinogenesis. Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Mammalian lignans and genistein decrease the activities of aromatase and 17beta-hydroxysteroid dehydrogenase in MCF-7 cells.

J Steroid Biochem Mol Biol. Flavonoid effects relevant to cancer. J Nutr. Catechol estrogen quinones as initiators of breast and other human cancers: implications for biomarkers of susceptibility and cancer prevention. Biochim Biophys Acta. The red clover Trifolium pratense isoflavone biochanin A modulates the biotrans-formation pathways of 7,dimethylbenz[ a ]anthracene.

Br J Nutr. Differential inhibition and inactivation of human CYP1 enzymes by trans-resveratrol: evidence for mechanism-based inactivation of CYP1A2. J Pharmacol Exp Ther. Inhibitory actions of genistein in human breast cancer MCF-7 cells. Resveratrol is a selective human cytochrome P 1A1 inhibitor.

Biochem Biophys Res Commun. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem J. Chemopreventive effects of soy protein and purified soy isoflavones on DMBA-induced mammary tumors in female Sprague-Dawley rats.

Nutr Cancer. Modest hormonal effects of soy isoflavones in postmenopausal women. J Clin Endocrinol Metab. Inhibition of 5 alpha-reductase in genital skin fibroblasts and prostate tissue by dietary lignans and isoflavonoids. J Endocrinol. Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat.

Resveratrol induces apoptosis and inhibits angiogenesis in human breast cancer xenografts in vivo. Cancer Lett. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor.

Phytoestrogens and the risk of breast cancer: a review of the literature. Int J Fertil Womens Med. Inactivation of NF-kappaB by genistein is mediated via Akt signaling pathway in breast cancer cells. Metabolism of apigenin and related compounds in the rat. Metabolite formation in vivo and by the intestinal microflora in vitro.

Effect of daidzein on cell growth, cell cycle, and telomerase activity of human cervical cancer in vitro. Int J Gynecol Cancer. The estrogen receptor betaisoform ERbeta of the human estrogen receptor modulates ERalpha transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Arch Pharm Res. Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast.

Phytoestrogens induce differential estrogen receptor alpha- or beta-mediated responses in transfected breast cancer cells.

Exp Biol Med Maywood ; 8 — Prepubertal exposure to zearalenone or genistein reduces mammary tumorigenesis. A large scale cohort study on the effect of life styles on the risk of cancer by each site [in Japanese] Gan No Rinsho. Contribution of a long-term prospective cohort study to the issue of nutrition and cancer with special reference to the role of alcohol drinking. Prog Clin Biol Res. Occurrence of breast cancer in relation to diet and reproductive history: a case-control study in Fukuoka, Japan.

Natl Cancer Inst Monogr. A large-scale, hospital-based case-control study of risk factors of breast cancer according to menopausal status.

Jpn J Cancer Res. Estrogenic effects of genistein on the growth of estrogen receptor-positive human breast cancer MCF-7 cells in vitro and in vivo. Expression profiling of the estrogen responsive genes in response to phytoestrogens using a customized DNA microarray. FEBS Lett. Inhibition of aromatase activity by flavonoids. Soy isoflavones increase latency of spontaneous mammary tumors in mice.

Genistein stimulates growth of human breast cancer cells in a novel, postmenopausal animal model, with low plasma estradiol concentrations. Effects of dietary daidzein and its metabolite, equol, at physiological concentrations on the growth of estrogen-dependent human breast cancer MCF-7 tumors implanted in ovariectomized athymic mice.

Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Genistein enhances N -nitrosomethylurea-induced rat mammary tumorigenesis. Reflections on the discovery and significance of estrogen receptor beta. Endocr Rev. Phytoestrogens modulate binding response of estrogen receptors alpha and beta to the estrogen response element.

J Agric Food Chem. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta.

The specific role of isoflavones on estrogen metabolism in pre-menopausal women. Mutat Res. Protection against breast cancer with genistein: a component of soy.

Am J Clin Nutr. Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity. Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxy-steroid dehydrogenase activities and human breast cancer cells. Life Sci. Aromatase and 17beta-hydroxysteroid dehydrogenase inhibition by flavonoids. Involvement of a post-transcriptional mechanism in the inhibition of CYP1A1 expression by resveratrol in breast cancer cells. Biochem Pharmacol.

Estrogenic and genotoxic potential of equol and two hydroxylated metabolites of daidzein in cultured human Ishikawa cells. Toxicol Lett. Cellular functions of the plasma membrane estrogen receptor. Trends Endocrinol Metab. Cloning and expression of a novel tissue specific 17beta-hydroxysteroid dehydrogenase. Endocr Res. Inhibition of nuclear factor kappaB activation in PC3 cells by genistein is mediated via Akt signaling pathway. Clin Cancer Res.

A homogeneous in vitro functional assay for estrogen receptors: coactivator recruitment. Mol Endocrinol. Decreased ovarian hormones during a soya diet: implications for breast cancer prevention. Increased urinary excretion of 2-hydroxyestrone but not 16alpha-hydroxyestrone in premenopausal women during a soya diet containing isoflavones.

Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells.

J Cell Physiol. Estrogen receptor alpha mediates the proliferative but not the cytotoxic dose-dependent effects of two major phytoestrogens on human breast cancer cells. Purification and characterization of nuclear type II [ 3 H]estradiol binding sites from the rat uterus: covalent labeling with [ 3 H]luteolin. Membrane-associated binding sites for estrogen contribute to growth regulation of human breast cancer cells.

A randomized isoflavone intervention among premenopausal women. Cancer Epidemiol Biomarkers Prev. Med Hypotheses. The molecular determinants of estrogen receptor pharmacology.

Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings. J Natl Cancer Inst. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Toxicol In Vitro. Interaction of phytoestrogens with estrogen receptors alpha and beta.

Biol Pharm Bull. Phytoestrogen concentrations in serum from Japanese men and women over forty years of age. Toxicol Sci. Prepubertal genistein exposure suppresses mammary cancer and enhances gland differentiation in rats. In vitro effects of diethylstilbestrol, genistein, 4- tert -butylphenol, and 4- tert -octylphenol on steroidogenic activity of isolated immature rat ovarian follicles.

Toxicol Appl Pharmacol. Gene expression profile induced by 17alpha-ethynyl estradiol, bisphenol A, and genistein in the developing female reproductive system of the rat.

Effect of soymilk consumption on serum estrogen concentrations in premenopausal Japanese women. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. A review of the effects and mechanisms of polyphenolics in cancer. Crit Rev Food Sci Nutr. Breast cancer and diet among the Japanese in Hawaii. Breast cancer in Caucasian and Japanese women in Hawaii. Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients.

Phytoestrogens and breast cancer risk. Review of the epidemiological evidence. Breast Cancer Res Treat. Estrogen receptors and cell signaling [Letter] Science.

Estrogen and growth factor receptor interactions in human breast and non-small cell lung cancer cells. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer. Ethnic differences in post-menopausal plasma oestrogen levels: high oestrone levels in Japanese-American women despite low weight.

Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosaluteal cells. Phytoestrogens and breast cancer—promoters or protectors? Endocr Relat Cancer. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor ER alpha and ERbeta. Induction and inhibition of aromatase CYP19 activity by natural and synthetic flavonoid compounds in HR human adrenocortical carcinoma cells.

Prepubertal resveratrol exposure accelerates N -methyl- N -nitrosourea-induced mammary carcinoma in female Sprague-Dawley rats. Hormonal and genotoxic activity of resveratrol. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha.

Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Am J Surg Pathol. Genistein exerts multiple suppressive effects on human breast carcinoma cells. Inhibition of CYP1A1 enzyme activity in mouse hepatoma cell culture by soybean isoflavones. Chem Biol Interact.

Identification of nuclear type II [ 3 H]estradiol binding sites as histone H4. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Phytoestrogens: end of a tale? Ann Med. Estrogen receptor beta inhibits 17beta-estradiol-stimulated proliferation of the breast cancer cell line T47D.

Utilization of oxygen and reduced nicotinamide adenine dinucleotide phosphate by human placental microsomes during aromatization of androstenedione. Meta-analysis of soy intake and breast cancer risk. Comparison of plasma and urinary phytoestrogens in Japanese and Finnish women by time-resolved fluoroimmunoassay. Breast cancer Cancer Surv. Pharmaceutical prospects of phytoestrogens. Endocr J. Attenuation of mitogen-and stress-activated protein kinasedriven nuclear factor-kappaB gene expression by soy isoflavones does not require estrogenic activity.

The stimulation of cell proliferation by quercetin is mediated by the estrogen receptor. Mol Nutr Food Res. Inhibition of 7,dimethylbenz a anthracene- and N -nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Dietary intake and sources of isoflavones among Japanese. The red wine polyphenol resveratrol displays bilevel inhibition on aromatase in breast cancer cells.

Acute and chronic effects of genistein, tyrphostin and lavendustin A on steroid synthesis in luteinized human granulosa cells. Hum Reprod.

Phytoestrogens and breast cancer | The American Journal of Clinical Nutrition | Oxford Academic

Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. In this brief review the action of phytoestrogens on oestrogen receptors, cell signalling pathways, regulation of the cell cycle, apoptosis, steroid synthesis and epigenetic events in relation to breast cancer are discussed.

Such effects on growth may be through phytoestrogens inhibiting cell signalling pathways. Phytoestrogens have also been shown to inhibit cyclin D1 expression but increase the expression of cyclin-dependent kinase inhibitors p21 and p27 and the tumour suppressor gene p Finally the effects of phytoestrogens on breast cancer may be mediated by their ability to inhibit local oestrogen synthesis and induce epigenetic changes. Core tip: Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer.

Phytoestrogens are naturally occurring plant compounds which are structurally similar to oestrogens and can have weak oestrogenic actions. The link between breast cancer and phytoestrogens arose from the early epidemiologal evidence showing that the incidence of breast cancer is lower in Asian populations who consume high dietary concentrations of soy products which have a high isoflavonone content[ 1 , 2 ].

This fuelled the widespread belief that consumption of soy foods reduces the risk of breast cancer and other hormone dependent cancers and led to further research on the protective effects of many other phytoestrogens[ 3 , 4 ]. This review will focus on the action of phytoestrogens on oestrogen receptors and cell signalling pathways, their regulation of the cell cycle and apoptosis, inhibition of steroidogeneic enzymes and induced epigenetic changes. In foods phytoestrogens are present as mixtures and are usually found as biologically inactive glycoside conjugates containing glucose or carbohydrate moieties.

Thus not only will dietary factors contribute to phytoestrogen intake but also individual variations in metabolism. Once absorbed the aglycone phytoestrogens are rapidly conjugated to glucuronic acid and to a lesser extent sulphuric acid in the hepatic circulation. They are then de-conjugated prior to excretion with urinary concentrations increasing in parallel to consumption[ 14 ].

One may then argue what is the relevance of in vitro studies showing that only high micromolar doses of unconjugated phytoestrogens can inhibit the growth the breast cancer cells, inhibit oestrogen-dependent gene transcription or inhibit cell signalling pathways?

Similarly in vivo studies have only shown that dietary supplements far in excess of those consumed with an Asian diet had any effect on inhibiting experimentally-induced tumour growth and even this data is conflicting[ 16 , 18 , 19 ] and references therein. Different ways in which phytoestrogens may alter gene transcription. Cyclins are a family of proteins which regulate transition of the cell cycle through the G 1 , S, G 2 and metaphase M phases and, through coalescing with cyclin-dependent kinases CDKs , they initiate gene transcription controlling regulation of the cell cycle.

This would result in increased apoptosis and decreased proliferation[ 44 ]. The pro-apoptotic protein, Bax, is regulated positively by p53 whilst the anti-apoptotic protein, Bcl-2, is negatively regulated by p53[ 45 ].

There is, however, evidence that phytoestrogens can also inhibit steroid synthesis and this may be particularly significant in relation to the local production of oestrogens in breast tissue[ 53 ] and references therein. Hence initial treatments are directed towards reducing oestrogenic effects by inhibitors of oestrogen receptors and inhibitors of aromatase which converts androgens to active oestrogens[ 55 ].

The incidence of breast cancer increases with age despite the loss of ovarian hormones in post-menopausal women. However our study on human granulosa cells showed that low dose mixtures of three isoflavones in the nM range inhibited expression and activity of aromatase though a similar inhibition was only achieved with a single phytoestrogen at times the dosage[ 60 ]. Further studies are required to investigate mixtures of phytoestrogens as occurs through dietary means.

Over the last decade there has been an explosion in the number of studies concerning epigenetic changes and the development and progression of breast cancer[ 61 ] and not surprisingly these have included studies on the ability of phytoestrogens to alter the epigenome which could be useful in the prevention of cancer[ 61 - 63 ]. Epigenetic changes are defined as heritable changes in gene expression which do not involve mutations of DNA nucleotide sequences. Along with DNMTs are the methyl-CpG-binding domain family of proteins which bind to a methylated gene and can inhibit transcriptional activity by altering chromatin structure.

The reverse occurs when histone proteins become deacetylated and this reaction is catalysed by histone deacetylases HDACs. In biopsies of human breast tissue specific DNMT transcripts were increased in cells taken from the tumourous tissue compared to adjacent normal breast tissue and parallel studies showed that treatment of breast cancer cells lines with genistein, resveratrol, curcumin and EGCC also reduced the mRNA of the same DNMTs[ 70 ].

It is clear that both nutrition and exposure to phytoestrogens and other phytochemicals can have dramatic effects on epigenetic events and that these may become heritable through transgenerational mechanisms. Thus their impact on both disease and the health of future generations needs to be carefully considered. Phytoestrogens have multiple targets within cells and whilst acute studies with supraphysiological doses of these compounds indicate that they may inhibit the development and progression of breast cancer, lower doses have been shown to promote the growth of breast cancer cells in vitro and experimentally induced tumours in vivo.

However their multiple targets in breast cancer cells and their ability to modulate epigenetic events associated with breast cancer and prevention may lead to new, non-toxic therapeutic approaches through development of highly specific and long-acting analogues of phytoestrogens.

National Center for Biotechnology Information , U. World J Clin Oncol. Published online Oct Author information Article notes Copyright and License information Disclaimer. Author contributions: Bilal I, Chowdhury A, Davidson J were MBBS project students in my laboratory and contributed towards collecting and assessing the references and synthesising the available data; Whitehead S wrote the review based on the students assessment.

All rights reserved. This article has been cited by other articles in PMC. Abstract Phytoestrogens have multiple actions within target cells, including the epigenome, which could be beneficial to the development and progression of breast cancer. Table 1 Major classes of phytoestrogens and their common dietary sources. Open in a separate window. Figure 1. Figure 2. References 1. Phytoestrogens and breast cancer prevention: possible mechanisms of action. Environ Health Perspect.

Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutr Clin Pract. Gikas PD, Mokbel K. Phytoestrogens and the risk of breast cancer: a review of the literature. Int J Fertil Womens Med. Pelekanou V, Leclercq G. Recent insights into the effect of natural and environmental estrogens on mammary development and carcinogenesis. Int J Dev Biol. Do phytoestrogens reduce the risk of breast cancer and breast cancer recurrence? What clinicians need to know.

Eur J Cancer. Phytoestrogens and breast cancer: a complex story. Is soy consumption good or bad for the breast? J Nutr. Phytoestrogens: perpetrators or protectors? Future Oncol. Analytical and compositional aspects of isoflavones in food and their biological effects. Mol Nutr Food Res. Patisaul HB, Jefferson W. The pros and cons of phytoestrogens.

Front Neuroendocrinol. Isoflavones: estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health.

Exp Biol Med Maywood ; — Controversies concerning the use of phytoestrogens in menopause management: bioavailability and metabolism. Urinary isoflavonoid excretion in humans is dose dependent at low to moderate levels of soy-protein consumption. Am J Clin Nutr. Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women Oxford arm of the European Prospective Investigation into Cancer and Nutrition Br J Nutr.

Leclercq G, Jacquot Y. Interactions of isoflavones and other plant derived estrogens with estrogen receptors for prevention and treatment of breast cancer-considerations concerning related efficacy and safety.

J Steroid Biochem Mol Biol. Rice S, Whitehead SA. Phytoestrogens and breast cancer — promoters or protectors? Endocr Rel Cancer. Endocrine-active chemicals in mammary cancer causation and prevention. Mechanisms underlying the dualistic mode of action of major soy isoflavones in relation to cell proliferation and cancer risks.

The different roles of ER subtypes in cancer biology and therapy. Nat Rev Cancer. Clinical significance of estrogen receptor beta in breast cancer. Cancer Chemother Pharmacol. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Disposition of soy isoflavones in normal human breast tissue. Estrogen receptors: how do they signal and what are their targets. Physiol Rev. Shimizu M, Weinstein IB. Modulation of signal transduction by tea catechins and related phytochemicals.

Mutat Res. Barnes S. The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products.

Phytoestrogens for breast cancer