Molecular Mechanism of Action of Genistein and Related Phytoestrogens in Estrogen Receptor Dependent and Independent Growth of Breast Cancer Cells

During the 3 years of my pre-doctoral research supported by the U.S. Armys Breast Cancer Research Program, I studied estrogen receptor ER-dependent and -independent effects of five structurally related phytoestrogens on breast cancer cell growth and apoptosis. Our studies showed that genistein binds to the ER with lower affinity compared to estradiol. However, genistein-bound ER is a 4S monomeric protein, while estradiol-bound ER is multimeric in our sucrose density gradient experiments. We also showed that genistein-ERbeta complex bound to the consensus estrogen responsive element ERE with high affinity. In contrast, genistein bound to ERalpha did not significantly bind to the ERE. These results suggest that genistein and estradiol exert different effects on ER-mediated functions. In ER-negative cells, genistein and quercetin inhibited cell growth and induced apoptosis in a dose-dependent manner. Daidzein, kaempferol and biochanin A were less effective. The mechanism of growth inhibition in ER-positive and ER-negative breast cancer cells by genistein and quercetin included G2M cell cycle arrest and alterations in cyclin B1 protein. Our results suggest that genistein and quercetin may be developed as chemotherapeutic agents against treatment of ER-negative tumors.