Prostate cancer presents a difficult problem. The key responsible tumor suppressor genes have not been definitively identified, and there is intense investigation to improve diagnostic and therapeutic approaches to this disease. Our laboratory has focused on the field of nuclear receptors, making critical contributions to the identification of corepressors and coactivators proved to be required for the actions of retinoic acid and estrogen receptors in normal cell lines, and has applied our expertise in this area and to the problems of prostate cancer. Here the actions of androgen receptor and of PPARy, provide an opportunity for understanding drug resistance and formulating the programs of treatment, based on the actions of the corepressor complex and investigation of prostate specific coactivators also could provide novel targets for diagnostic and therapeutic intervention. We have hypothesized that androgen receptor antagonists used in the treatment of prostate cancer causes recruitment of a corepressor complex to the androgen receptor, which underlies their inhibitory actions, and that clinical resistance of the antagonists reflects a failure, due to several alternate mechanisms, of corepressor recruitment to the androgen receptor. In the past three years, using a genetic model approach, we have provided evidence supporting the hypothesis that androgen receptor antagonists require the nuclear receptor corepressor (N-CoR) to inhibit androgen receptor activity. Thus, in cells in which the N-CoR gene is deleted, the ligands act as full agonists. In prostate cancer developing resistance to androgen antagonists is universal. We hypothesize that this usually reflects modifications and alterations in N-CoR ? androgen receptor interactions and in N-CoR function. We have discovered two novel N-CoR complexes and have defined the molecular mechanisms that lead to N-CoR interactions and translocation mediating specific transcription events. Based on these findings, we suggest that by defining the molecular mechanisms by which N-CoR is regulated we can provide new approaches to prevent resistance.
Our Specific Aims therefore are: 1.) to begin to define the pathways and molecules that modulate N-CoR actions, and events that lead to resistance to androgen receptor antagonists by altered expression and/or regulation of the components of a specific corepressor complex, both in vitro and in vivo and II.) to identify novel prostate corepressors and coactivators that underlie regulation of metastasis suppressor genes in prostate cancer. The major research methods used for both Specific Aims will involve molecular biological, cell biological, biochemical, and genetic approaches.
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