Genistein and apigenin are phytoestrogens present in commercial preparations used for the treatment of postmenopausal symptoms. In this study, we assessed the influence of these compounds on mammary tumor growth. Both compounds stimulate the proliferation of MCF-7 and T47D cells [estrogen receptor alpha (ERalpha-positive)], but do not stimulate the proliferation of an ERalpha-negative cell line (MDA-MB-435 cells). Genistein appeared more efficient in this regard due to its higher binding affinity for ERalpha, a property explained by a structural analysis of the binding of these compounds to the ERalpha's ligand binding domain. As previously described for estradiol (E(2)), genistein and apigenin down regulated ERalpha and enhanced estrogen response element (ERE)-dependent gene expression. The additional finding that genistein antagonizes the anti-proliferative effect of hydroxytamoxifen suggests phytoestrogens may be detrimental in women with breast cancer who are being treated with tamoxifen. In addition, because of their ability to stimulate breast cell growth, the widespread use of phytoestrogens in postmenopausal women could be detrimental.