Phytoestrogens and prevention of breast cancer: The contentious debate.

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. Phytoestrogens can bind weakly to oestrogen receptors (ERs) and some have a preferential affinity for ERβ which can inhibit the transcriptional growth-promoting activity of ERα.

Aromatase expression in abdominal omental/visceral and subcutaneous fat depots: a comparison of pregnant and obese women.

Objective: To investigate total and promoter expression of aromatase in subcutaneous and omental (visceral) fat and compare this expression in pregnant and obese women.

Design: Cross-sectional study.

Setting: Academic hospital.

Action of metformin on the insulin-signaling pathway and on glucose transport in human granulosa cells.

Context: Hyperinsulinemia in polycystic ovary syndrome is widely treated with the insulin sensitizer metformin, which, in addition to its systemic effects, directly affects the ovarian insulin-stimulated steroidogenesis pathway.

Objective: Our aim was to investigate the interaction of metformin with the other insulin-stimulated ovarian pathway, namely that leading to glucose uptake.

Design: Human granulosa-luteal cells were cultured with metformin (10(-7) M), insulin (10 ng/ml) or metformin and insulin (met + ins) combined.

Long-term genistein treatment of MCF-7 cells decreases acetylated histone 3 expression and alters growth responses to mitogens and histone deacetylase inhibitors.

Defects in epigenetic regulation of gene transcription play an important role in carcinogenesis of the breast and other tissues. The two most widely studied epigenetic changes are DNA methylation and acetylation of histone proteins and inhibition of these processes inhibits growth in breast cancer cell lines. These data coupled with the evidence that fetal and neonatal exposure to oestrogenic substances may lead to epigenetic changes that predispose or protect against the development of breast cancer in later life formed the basis for this study.

Evidence that low-dose, long-term genistein treatment inhibits oestradiol-stimulated growth in MCF-7 cells by down-regulation of the PI3-kinase/Akt signalling pathway.

The reduced incidence of breast cancer in certain Eastern countries has been attributed to high soy diets although this evidence is simply epidemiological. One of the major constituents of soy is genistein, but paradoxically this phytoestrogen binds to oestrogen receptors and stimulates growth at concentrations that would be achieved by a high soy diet, but inhibits growth at high experimental concentrations. To determine the effects of low-dose, long-term genistein exposure we have cultured MCF-7 breast cancer cells in 10 nM genistein for 10-12 weeks and investigated whether or not this long-term genistein treatment (LTGT) altered the expression of oestrogen receptor alpha (ERalpha) and the activity of the PI3-K/Akt signalling pathway.

Phytoestrogens oestrogen synthesis and breast cancer.

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

Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and anti-Müllerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries.

Context: Recent evidence indicates that the increase in follicle numbers seen in polycystic ovary syndrome occurs early in folliculogenesis, with androgens being a likely causative candidate. In primates and sheep, androgen excess in utero results in ovarian changes similar to those in polycystic ovary syndrome. There is also increasing interest in the role of anti-Müllerian hormone (AMH) in early folliculogenesis because AMH knockout mice have an early depletion of their stock of primordial follicles.

Phytoestrogens and breast cancer--promoters or protectors?

The majority of breast cancers are oestrogen dependent and in postmenopausal women the supply of oestrogens in breast tissue is derived from the peripheral conversion of circulating androgens. There is, however, a paradox concerning the epidemiology of breast cancer and the dietary intake of phytoestrogens that bind weakly to oestrogen receptors and initiate oestrogen-dependent transcription. In Eastern countries, such as Japan, the incidence of breast cancer is approximately one-third that of Western countries whilst their high dietary intake of phytoestrogens, mainly in the form of soy products, can produce circulating levels of phytoestrogens that are known experimentally to have oestrogenic effects.

Ethanolic extracts of black cohosh (Actaea racemosa) inhibit growth and oestradiol synthesis from oestrone sulphate in breast cancer cells.

Extracts of black cohosh (Actaea racemosa) and soy are used as 'natural' alternatives to conventional hormone replacement therapy (HRT) and there is some evidence that soy may protect against breast cancer by inhibiting the production of active oestrogens. This study compares the action of ethanolic extracts of black cohosh (BCE) and genistein on growth and enzyme activity in MCF-7 and MDA-MB-123 breast cancer cells. BCE inhibited growth at the two highest doses tested, i.

Granulosa cell production of anti-Müllerian hormone is increased in polycystic ovaries.

Context: There has been renewed interest in anti-Müllerian hormone (AMH) because of its role in the ovary. Data on its actions are sparse, but it appears to inhibit follicle growth. Interestingly, serum AMH is two to three times higher in women with polycystic ovary (PCO) syndrome than women with normal ovaries.

Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells.

There is evidence that certain phytoestrogens inhibit aromatase, the enzyme that converts androgens to oestrogens. Kinetic studies in cell-free preparations show that they may inhibit aromatase by competitive binding to the enzyme, but there is a paucity of studies investigating longer-term effects of phytoestrogens on the expression of steroidogenic enzymes. This study tested the hypothesis that phytoestrogens could reduce aromatase activity by down-regulation of its expression.

Endocrine-disrupting chemicals as modulators of sex steroid synthesis.

Endocrine-disrupting chemicals (EDCs) are typically identified as compounds that can interact with oestrogen or androgen receptors and thus act as agonists or antagonists of endogenous hormones. Growing evidence shows that they may also modulate the activity/expression of steroidogenic enzymes. These are expressed not only in the adrenal glands and gonads but also in many tissues that have the ability to convert circulating precursors into active hormones.

Dose-response effects of phytoestrogens on the activity and expression of 3beta-hydroxysteroid dehydrogenase and aromatase in human granulosa-luteal cells.

There is evidence that certain phytoestrogens can inhibit key steroidogenic enzymes although most studies have been carried out on microsomal or purified enzyme preparations, some using cell lines. This study was designed to test the hypothesis that low doses of phytoestrogens, at concentrations that would be attained through the diet, could inhibit 3beta-hydroxysteroid dehydrogenase (HSD) and/or aromatase in primary cultures of human granulosa-luteal (GL) cells and that this effect was due to a decrease in the expression of these proteins. Based on published evidence, eight compounds were selected for investigation and these included the flavones apigenin and quercetin, the isoflavones genistein, biochanin A and daidzein, the lignans, enterodiol and enterolactone, and the mycotoxin zearalenone.

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

Background: Phytoestrogens, including genistein and other inhibitors of tyrosine kinases (TKs), inhibit specific steroidogenic enzymes. This study was designed to compare the effects of genistein, with two other TK inhibitors, on steroid synthesis in human granulosa luteal (GL) cells and to identify which steroidogenic enzymes they may affect.

Methods: GL cells, obtained from women undergoing IVF procedures, were cultured for various periods of time with and without substrates for progesterone and estradiol synthesis, in the presence or absence of the TK inhibitors.