? ? Prostate cancer is the second most common cause of cancer related deaths in American men due to the lack of effective therapeutics for hormone-refractory prostate cancer. Estrogens play important roles in normal growth, differentiation and development of the prostate. Administration of pharmacological doses of estrogen induces squamous metaplasia in the prostates of various mammalian species. Epidemiological and experimental data indicate that estrogens are the key mediators of benign prostatic hyperplasia (BPH) development and prostate carcinogenesis. The discovery of ER? isoforms in rat and human prostates has created a new dimension in estrogen signaling and led to the hypothesis that ER? is a novel target for prostate cancer intervention. This hypothesis is based on the following observations: 1) ER? knockout mice exhibited epithelial cellular hyperplasia in the ventral prostate and eventually developed PIN (prostatic intraepithelial neoplasia) lesions whereas the prostate of ERa knock out mice appeared to be normal, 2) there was a linkage between ER? expression and the prognosis of prostate cancer. The flavone apigenin present in fruits, vegetables and tea has attracted intense interest due to its chemopreventive effects on prostate cancer. Although apigenin is known to have estrogenic activities, the exact mechanisms of how this compound exerts its antiproliferative effects on prostate cancer cells are largely unknown. In particular, it is not well investigated if and how their estrogenic properties play an important role in the context of their anti-prostate cancer activities. Recently, there is compelling evidence to support the notion that estrogens and phytoestrogens elicit different transcription activations by differential usage of ERa versus ER? and subsequently selective coregulator recruitment. This observation has prompted a drug discovery effort within the pharmaceutical industry to search for highly selective ligands of ER? as potential chemopreventive or therapeutic agents for prostate cancer. Based on these findings, we therefore hypothesize that apigenin exerts its antitumor effects partly via interaction with different homo- or heterodimeric version of ER subtypes, facilitate recruitment of specific sets of coregulators that confer selective transactivating potentials on different natural promoters. Thus the objectives of this application are (i) How does apigenin elicit distinct transcriptional actions from estrogens? (ii) Can the biological responses of different prostate cancer cells to apigenin be linked to its differential usage of ER? signaling pathways? ? ? ?
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