Mechanistic Study of Estrogen Receptor/Xenoestrogen Interaction in Cancer
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The proposed research aims to develop a multidisciplinary research program integrating the latest biophysics, analytical chemistry, cell assay platforms to dissect molecular mechanisms for the tissue selectivity of phytoestrogen. Phytoestrogens are the plant secondary metabolites that can interact with the estrogen receptors leading to various impacts on woman's health. The role of phytoestrogens in breast cancer development is still controversial, because previous researches have shown either beneficiary or detrimental effects on breast cancer depending on the model systems, different compounds, and populations that have been studied. It is therefore important to elucidate the structural and molecular mechanisms of phytoestrogen-induced downstream gene expression, to develop rapid methods to predict the pharmaceutical effects of a certain phytoestrogen, and to correlate the structural and molecular results with the pharmaceutical effects and tissue selectivity. We therefore propose to combine the latest HDX mass spectrometry with biochemical and cell-based assays to analyze the structure determinants for the phytoestrogen induced responses in estrogen receptor (ER), to develop and verify a rapid biochemical method for predicting the tissue selectivity and pharmacological effects of phytoestrogens based on HDX, and to investigate how the binding of ER with phytoestrogen could impact the downstream biological activities. The proposed research will shed light into the molecular mechanisms of phytoestrogen tissue selectivity, provide the practical methods to classify the phytoestrogens,provide chemical targets for crop(i.e. soybean) breeding and improvements, guide the use of phytoestrogen as active ingredients for functional food and alternative medicine for cancer treatment, and develop proper intake guidance toward consuming phytoestrogen containing food for cancer prevention.