Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation

Epidemiologic and experimental studies support the hypothesis that dietary estrogens from plant sources (phytoestrogens) may play a role in the preven tion of breast and prostate cancer. The molecular mechanisms for such chemo preventive effect are still unclear. We investigated the possibility that p hytoestrogens may bind differentially to estrogen receptor proteins (ER alp ha and ER beta) and affect the interactions of the ligand-ER complexes with different estrogen response element (ERE) sequences. We used fluorescence polarization to measure the binding affinities of genistein, coumestrol, da idzein, glyceollin, and zearalenone for human ER alpha and ER beta. Competi tion binding experiments revealed higher affinity of the phytoestrogens for ER beta than for ER alpha. Genistein [median inhibitory concentration 12nM ] is the most potent and has the same relative binding affinity for ER beta as 17 beta-estradiol. We also studied the effect of these phytoestrogens o n the ability of ER alpha and ER beta to associate with specific DNA sequen ces (EREs). The direct binding of human recombinant estrogen receptors to f luorescein-labeled EREs indicates that phytoestrogens can cause conformatio nal changes in both human ERs, which results in altered affinities of the c omplexes for the ERE from the Xenopus vitellogenin A2 gene and an ERE from the human pS2 gene.