Androgen Receptor Associated Proteins in Prostate Cancer

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DESCRIPTION (provided by applicant): Like most cancers, prostate carcinogenesis involves a multistep progression from precancerous cells to cells that proliferate locally in an unregulated fashion and then metastasize. Observations from androgen ablation treatment of prostate cancer have shown that the androgen-signaling pathway is important for the growth and progression of prostate cancer. The growth-promoting effects of androgen are mediated mostly through the androgen receptor (AR). AR is a member of the nuclear hormone receptor family and plays a central role in the development of the normal prostate and in prostate cancer through the regulation of ligand dependent transcription. Understanding the mechanisms by which the AR regulates gene expression should, therefore, provide insight into abnormalities that may contribute to the development of prostate cancer and provide possible targets for future treatment. In the past four years, we and others have demonstrated that the function of AR is regulated by other transcriptional activators, repressors, and modulators. In particular, we recently identified three important, but distinct, AR-interacting proteins, which include a transcriptional activator, beta-catenin; a transcriptional repressor, TGIF; and a novel transcription factor, TAC10. Recent studies have shown that both beta-catenin and TGIF play critical roles in normal development and tumorigenesis through the Wnt and TGF-beta signaling pathways, respectively. TAC10 is a protein that was identified by a modified yeast one-hybrid system. It is selectively expressed in prostate cells and contains a potent transactivation domain. Based on this evidence, we hypothesize that these three factors are critical mediators in androgen signaling in prostate cells, and that their regulation or dysregulation are important in the pathogenesis of prostate cancer. Therefore, we propose several approaches to study the mechanisms by which these cofactors regulate AR action and to define the biological significance of these interactions in the development and progression of prostate cancer. The Specific Aims are as follows: (1) Examine the interaction between AR and beta-catenin in prostate cancer cells; (2) Determine how TGIF regulates AR activity in prostate cancer cells; (3) Study the biological roles of TAC 10 in modulating AR-mediated transcription.