The androgen receptor (AR) plays a central role in prostate cancer (PCa) development and progression, and androgen ablation therapy is still the standard systemic therapy for metastatic PCa. Unfortunately, patients invariably relapse with a more aggressive form of PCa that has been termed hormone refractory or androgen independent PCa. However, the AR and many AR regulated genes are still expressed at high levels in androgen independent PCa, indicating that the AR remains transcriptionally active. One approach to treat androgen independent PCa may be the use of drugs that enhance AR recruitment of nuclear receptor transcriptional corepressors, in particular NCoR and SMRT, which would have the potential to actively repress the expression of AR regulated genes. We have shown that the AR interacts with NCoR, and that this interaction can be markedly enhanced by mifepristone, a steroidal antagonist that similarly enhances NCoR binding by the progesterone and glucocorticoid receptors. Mifepristone provides a """"""""proof of principle"""""""" that the AR-NCoR interaction can be enhanced, and suggests a novel mechanism for the stabilization of antagonist binding that may be valuable in the further development of high affinity AR antagonists or partial agonists. However, the molecular basis for AR recruitment of NCoR or SMRT to endogenous AR regulated genes, and how these AR-corepressor complexes modulate chromatin structure and gene expression remain to be determined. Therefore, the overall major objective of this proposal is to test the hypotheses that NCoR (or SMRT) recruitment to endogenous AR regulated genes can be enhanced by particular antagonists and mediate the active repression of endogenous AR regulated genes in PCa cells.
Aim 1 is to identify the molecular interactions that mediate NCoR binding to the mifepristone liganded AR and recruitment to AR regulated genes.
Aim 2 is to determine how NCoR recruitment to endogenous AR regulated genes by the antagonist (bicalutamide or mifepristone) liganded AR modulates chromatin structure and gene expression.
Aim 3 is to develop stable cell lines for high throughput drug screening to identify AR antagonists that can further enhance NCoR recruitment and suppress the expression of AR regulated genes. ? ? ? ?
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