Coactivators in Androgen-Refractory Prostate Cancer

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DESCRIPTION (Provided by the applicant) Hormonal therapy is the most common treatment for advanced prostate cancer. However, patients usually die of an androgen-refractory form of the disease with no hope for further treatment. Our laboratory has demonstrated that disruption of the androgen receptor (AR) inhibits proliferation of androgen-refractory PCa cells. Moreover, AR can be activated by nonandrogenic factors, such as IL-6 and IGF-I. This has accentuated the need to study the molecular mechanisms underlying the activation of the AR in androgen-refractory PCa. Thus, we have focused our attention on the role of coregulators in androgen-independent activation of the AR. Studies suggest that the coactivators CBP and p300 are required for IL-6-mediated transactivation of the AR. CBP appears to act by binding to the AR; p300 appears to act by binding to STAT3, a component of the IL-6 pathway. Additionally, two core components of the human SWI/SNF complex, BAF170 and BAF60b, are overexpressed in androgen-refractory PCa cells. From these data we hypothesize that IL-6-induced transactivation of AR is mediated by the AR-STAT3 interaction bar recruitment of transcriptional coregulators. including CBP, p300 and components of the SWI/SNF complex. To test this hypothesis, we propose to (1) determine if the CBP/AR complex provides a foundation for IL-6-induced transactivation of the AR; (2) determine if the recruitment of the p300/STAT3 complex into AR is a key factor in IL-6-induced transactivation of the AR; (3) determine if the core components of the SWI/SNF complex facilitate IL-6-induced transactivation of the AR. These studies should enhance our understanding of androgen-refractory prostate cancer and may identify new therapeutic targets for this disease.