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The androgen receptor (AR) primarily binds androgen ligands such as testosterone (T) and dihydrotestosterone (DHT) and then acts as a nuclear transcription factor to facilitate appropriate expression of androgen-responsive genes (ARGs). Indeed, AR function is necessary for the normal growth, terminal differentiation and function of male urogenital structures, which includes the prostate gland. Prostate tumor cells likely exploit androgen action for survival since most are initially responsive to androgen ablation therapy. However, following such therapy a majority of prostate cancers eventually return as a more aggressive, hormone-withdrawal resistant form. Given that levels of circulating T fall with ageing while the incidence of prostate cancer rises, we have proposed that decreasing circulating T in fact provides selective advantage to cells in which the AR axis is corrupted. Such corruption can take place through a number of mechanisms including AR amplification, mutation, and ligand-independent activation. We have previously shown that AR is spontaneously mutated in somatic cells of primary prostate cancer in mice and man and that transgenics expressing an AR with a point mutation (E231G) developed prostate cancer whereas mice carrying a transgene encoding the wildtype AR (ARwt) did not. This study proved that specific AR mutations could drive CaP progression. To investigate the mechanism by which this may occur, expression profiling was performed using Affymetrix mouse 230 2.0 arrays on RNA isolated from prostate tissues of mice expressing a transgene encoding either ARwt, AR(E231G) of AR(T857A). When comparing E231G and T857A to normal mice, 524 and 436 genes were found to be differentially regulated >2 fold, respectively; whereas 139 and 115 genes were differentially regulated when comparing these mutants to ARwt. 54 genes were differentially regulated >2 fold when comparing E231G to T857A, implicating differential cofactor recruitment and promoter-specificity. To determine the role of particular AR-cofactor pairs in regulating ARG promoter specificity, we are performing chromosome immunoprecipitation followed by microarray analysis to test the hypothesis that the AR transcriptome is altered in CaP as a consequence of alterations in AR cofactor recruitment. Supported by the Prostate Cancer Foundation, National Cancer Institute R01 CA73747

[Proc Amer Assoc Cancer Res, Volume 47, 2006]