Genistein's "ER-dependent and independent" actions are mediated through ERpathways in ER-positive breast carcinoma cell lines

Genistein, a natural flavone found in soy has been postulated to be respons ible for lowering the rate of breast cancer in Asian women. Our previous st udies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER -) human breast carcinoma lines suggesting that the mechanisms of these eff ects may be independent of ER pathways. In the present study however we pro vide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER- MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-indepe ndent" actions of genistein are mediated through ER pathways. Genistein's a ntiproliferative effects are estrogen dependent in these ER+ lines, being m ove pronounced in estrogen-containing media and in the presence of exogenou s 17-beta estradiol. Genistein also inhibits the expression of ER-downstrea m genes including pS2 and TGF-beta in these ER+ fines and this inhibition i s also dependent on the presence of estrogen. Genistein inhibits estrogen-i nduced protein tyrosine kinase (PTK) activity. Genistein is only a weak tra nscriptional activator and actually decreases ERE-CAT levels induced by 17- beta estradiol in the ER+ lines. Genistein also decreases steady state ER m RNA only in the presence of estrogen in the ER+ lines thereby manifesting a nother suppression of and through the ER pathway. Our observations resurrec t the hypothesis that genistein functions as a "good estrogen" in ER+ breas t carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrog en" action of genistein is most relevant to our understanding of chemopreve ntion.