Genistein, Soy Isoflavones II and Breast Cancer ER+

Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary
There has been considerable investigation of the potential for soyfoods to reduce risk of cancer, and in particular cancer of the breast. Most interest in this relationship is because soyfoods are essentially a unique dietary source of isoflavones, compounds which bind to estrogen receptors and exhibit weak estrogen-like effects under certain experimental conditions. In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns – based mostly on in vitro and rodent data – that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. In this analysis and commentary we attempt to outline current concerns regarding the estrogen-like effects of isoflavones in the breast focusing primarily on the clinical trial data and place these concerns in the context of recent evidence regarding estrogen therapy use in postmenopausal women. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. Although relatively limited research has been conducted, and the clinical trials often involved small numbers of subjects, there is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The epidemiologic data are generally consistent with the clinical data, showing no indication of increased risk. Furthermore, these clinical and epidemiologic data are consistent with what appears to be a low overall breast cancer risk associated with pharmacologic unopposed estrogen exposure in postmenopausal women. While more research is required to definitively allay concerns, the existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue.
Messina MJ, Wood CE. Nutrition Journal 2008, 7:17 doi:10.1186/1475-2891-7-17

Clinical significance of estrogen receptor β in breast cancer
Ever since the estrogen receptor (ER) β was discovered in 1996, we have been trying to determine its value as a prognostic and/or predictive factor in breast cancer and its potential as a novel target for pharmacological intervention. Recent progress in cellular experiments has shown that ERβ works as counter partner of ERα through inhibition of the transactivating function of ERα by heterodimerization, distinct regulation on several specific promoters by ERα or ERβ, and ERβ-specific regulated genes which are probably related to its anti-proliferative properties. Accumulated data from protein studies in breast cancer tissues indicate that positive expression of ERβ appears to correlate with a favorable prognosis. Although the number of studies is small, a positive response to tamoxifen treatment is observed in both ERα- and ERβ-positive populations. The significance of ERβ2/cx, a splicing variant of ERβ, remains controversial and needs to be analyzed in further studies. We postulate that a combined evaluation of ERβcx with progesterone receptor may help the stratification of ERα-positive breast cancer. Epidemiological studies of hormone replacement therapy and isoflavone (genistein) consumption indicate the possible contribution of ERβ-specific signaling in breast cancer prevention. A selective estrogen receptor modulator, which works as an antagonist of ERα and an agonist of ERβ, may be a promising chemo-preventive treatment.
Saji S, Hirose M, Toi M. Cancer Chemotherapy and Pharmacology Volume 56, Supplement 1, 21-26 2005 DOI: 10.1007/s00280-005-0107-3

Estrogen receptors alfa (ERalpha) and beta (ERbold italic beta) differentially regulate proliferation and apoptosis of the normal murine mammary epithelial cell line HC11
The mitogenic effect of 17beta-estradiol (E2) on the breast is mediated by estrogen receptor alfa (ERalpha), hence ERalpha antagonists are effective in the treatment of breast cancer. The possible use of estrogen receptor beta (ERbeta) as a target in treatment of breast cancer is under investigation. The mouse mammary cell line HC11 expresses both ERs and was used to study the role of the two receptors in proliferation. E2 had no effect on proliferation. The ERalpha-selective agonist 4,4′,4″-(4-propyl-(1H)-pyrazole-1,3,5-triyl)trisphenol (PPT) stimulated proliferation. The ERbeta-selective agonist 2,3-bis(4-hydroxy-phenyl)-propionitrile (DPN) inhibited cell growth and induced apoptosis. PPT upregulated while DPN downregulated cyclin D1 and proliferating cell nuclear antigen (PCNA). Upon inhibition of ERalpha expression with RNA interference, E2 caused a decrease in cyclin D1 and PCNA, and increased apoptosis. When ERbeta expression was blocked, E2 induced proliferation and cells gained the capacity to grow in soft agar. In summary, in HC11 mammary epithelial cells, ERalpha drives proliferation in response to E2 while ERbeta is growth inhibitory. The lack of effect of E2 on HC11 cell growth is the result of the combined actions of ERalpha (proliferation) and ERbeta (apoptosis). We suggest that use of ERbeta agonists will be a useful addition in treatment of breast cancer, which, at present, is only aimed at inhibition of ERalpha.
Helguero LA, et al. Oncogene (2005) 24, 6605–6616. doi:10.1038/sj.onc.1208807

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