119 DMBA = 7,12-dimethylbenz(a)anthracene; EGC = epigallocatechin; EGF = epidermal growth factor; EGCG = epigallocatechin-3 gallate; ER = oestrogen receptor; ERE = oestrogen response element; HRT = hormone replacement therapy; IGF = insulin-like growth factor; SRC = steroid receptor coactivator; TGF = transforming growth factor. Available online http://breast-cancer-research.com/content/6/3/119 IntroductionThe current mortality rate for premenopausal breast cancer is approximately fourfold higher in the Western World than in Far East Asian nations [1]. Migrants from Asia to the USA typically acquire a breast cancer risk associated with their host nation by the second generation, suggesting a direct influence of environmental rather than genetic factors [2,3]. The reduced prevalence of breast cancer in Far East Asian nations directly correlates with the consumption of a staple diet that is abundant in soy [4]. Asian populations consume an approximate mean daily soy intake of 10-50 g, declining to just 1-3 g in the USA. The recent adoption of a more westernized diet correlates with an increased breast cancer incidence in urban areas of Japan, Singapore and China [5]. Soycontaining foods are an abundant source of phytooestrogens, and research suggests that these compounds may exhibit chemoprotectant activity against a number of human cancers, including colon carcinoma and hormonedependent cancers of the breast and prostate [6]. This report focuses on the putative chemopreventive role of phyto-oestrogens in breast cancer, providing a comprehensive review of the published literature to date. Phyto-oestrogen classification and metabolismPhyto-oestrogens may be classified into a number of principal groups [2,[7][8][9]: the isoflavones (genistein, daidzein, biochanin A), the lignans (enterolactone, enterodiol), the coumestans (coumestrol) and the stilbenes (resveratrol). As illustrated in Fig. 1 AbstractPhyto-oestrogens are polyphenol compounds of plant origin that exhibit structural similarity to the mammalian steroid hormone 17β-oestradiol. In Asian nations the staple consumption of phytooestrogen-rich foodstuffs correlates with a reduced incidence of breast cancer. Human dietary intervention trials have noted a direct relationship between phyto-oestrogen ingestion and a favourable hormonal profile associated with decreased breast cancer risk. However, these studies failed to ascertain the precise effect of dietary phyto-oestrogens on the proliferation of mammary tissue. Epidemiological and rodent studies crucially suggest that breast cancer chemoprevention by dietary phyto-oestrogen compounds is dependent on ingestion before puberty, when the mammary gland is relatively immature. Phyto-oestrogen supplements are commercially marketed for use by postmenopausal women as natural and safe alternatives to hormone replacement therapy. Of current concern is the effect of phyto-oestrogen compounds on the growth of pre-existing breast tumours. Data are contradictory, with cell culture studies reporting both the oestrogenic st...
Two oestrogen receptors, ER alpha and ER beta, exist. While much is known about ER alpha, the role of ER beta is still undefined, especially at the protein level. The aim of this study was to determine the utility of seven ER beta antibodies (14C8, 8D5, PAI313, PPG5/10, N19, 9.88, and D7N) raised against different domains of ER beta in three commonly used laboratory applications, namely immunohistochemistry, western blot, and flow cytometry, using human breast material. For immunohistochemical analysis of frozen material, PAI313 and D7N gave stronger and more specific signals than 14C8, 8D5, and PPG5/10. In paraffin sections, 14C8, closely followed by PPG5/10, gave by far the most superior nuclear immunoreactivity, compared with the other antibodies tested. In general, flow cytometry results mirrored the immunohistochemistry data for paraffin sections, with antibodies ranked 14C8 > 8D5> or = PAI-313 > PPG5/10 >D7N. For western blotting, 8D5 and D7N yielded the strongest and most consistent bands, with weaker bands seen with the others. It is concluded that ER beta protein can be detected using specific antibodies. However, there is considerable variation between the specificity and application of these antibodies, highlighting the fact that careful optimization is required when selecting an antibody for use in a particular laboratory technique.
Women approaching menopause increasingly investigate alternatives to hormone replacement therapy. Plant phytoestrogens are being promoted as ''natural'' alternatives but there is a lack of substantive data to advocate their safe use in breast cancer patients receiving tamoxifen (TAM), or in those who have relapsed. The aim of our study was to investigate the proliferative effects and mode of action of the phytoestrogens genistein, daidzein and coumestrol on TAM-sensitive (-s) and resistant (-r) breast cancer cells under in vitro conditions designed to mimic the hormonal environment of the pre-and post-menopausal breast. At physiological concentrations (<10 lM) and under reduced estrogen (E2) conditions, genistein was mitogenic to TAM-s cells with TAM-r cells generally refractory. Daidzein and coumestrol were growth stimulatory irrespective of TAM sensitivity. Transcriptional activity was ERE-mediated. Combining phytoestrogens with E2 (simulating the pre-menopausal breast environment) had no effect on growth of TAM-s or TAM-r cells. Addition of 4-HT mimicked the hormonal environment in post-menopausal breast cancer patients receiving TAM. The growth inhibitory effects of 4-HT were abrogated in TAM-s cells when combined with genistein and coumestrol, and to a lesser extent, daidzein, where significant growth stimulatory effects were observed. In TAM-r cells, proliferation did not exceed control values. At phytoestrogen concentrations above 10 lM, growth inhibitory effects were seen, irrespective of estrogenic environment or cell sensitivity to TAM. Our in vitro data suggests that phytoestrogens could have potentially adverse mitogenic effects on tumour cells and should probably be avoided by patients who remain sensitive to TAM or in those with pre-existing and possibly undiagnosed breast tumours. ' 2006 Wiley-Liss, Inc. Key words: phytoestrogens; breast cancer; tamoxifenThe premature termination of the HABITS trial 1 and association of increased breast cancer with hormone replacement therapy (HRT) use in the Million Women Study 2 have cast doubt on the efficacy of HRT use in breast cancer patients. Improved survival of women with breast cancer has made the management of menopause (either natural or early induction by surgery, hormone therapy or chemotherapy) an important clinical issue. In view of the adverse publicity associated with HRT, to alleviate menopausal symptoms, women may now consider phytoestrogens, which are being increasingly promoted as ''natural'' alternatives to HRT. Phytoestrogens are polyphenols of plant origin with structural similarity to the steroid hormone 17b-estradiol (E2).3 They are abundant in soy-containing foods and converted into estrogenic substances by gut flora. In recent years they have become freely available as over-the-counter capsules from health food shops.Like their mammalian counterparts, phytoestrogen action is mediated by both -a and -b subtypes of oestrogen receptor (ER), although they show increased affinity for ERb. 4 Research suggests that phytoestrogens may be chemo...
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