Estrogen receptor β-selective transcriptional activity and recruitment of coregulators by phytoestrogens

Estrogens used in hormone replacement therapy regimens may increase the risk of developing breast cancer. Paradoxically, high consumption of plant-derived phytoestrogens, particularly soybean isoflavones, is associated with a low incidence of breast cancer. To explore the molecular basis for these potential different clinical outcomes, we investigated whether soybean isoflavones elicit distinct transcriptional actions from estrogens, Our results demonstrate that the estrogen 17 beta -estradiol effectively triggers the transcriptional activation and repression pathways with both estrogen receptors (ERs) ER alpha and ER beta. In contrast, soybean isoflavones (genistein, daidzein, and biochanin A) are ER beta -selective agonists of transcriptional repression and activation at physiological levels. The molecular mechanism for ER beta selectivity by isoflavones involves their capacity to create an activation function-2 surface of ER beta that has a greater affinity for coregulators than ER alpha. Phytoestrogens may act as natural selective estrogen receptor modulators that elicit distinct clinical effects from estrogens used for hormone replacement by selectively recruiting coregulatory proteins to ER beta that trigger transcriptional pathways.