Role of BAF57 in AR control and prostate cancer growth

Thomas Jefferson University, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the second leading cause of cancer death amongst men in the United States, as effective therapy for advanced cancers remains elusive. Disseminated prostatic adenocarcinomas are initially dependent on androgen for growth and survival;thus, the mainstay of therapy for this tumor type is ablation of androgen receptor (AR) function, either through direct AR inhibition or through inhibition of androgen synthesis. Although these lines of treatment are initially effective, recurrent tumors ultimately arise which are refractory to androgen ablation and AR inhibition. Clinical evidence strongly supports the concept that the AR is inappropriately reactivated in these recurrent tumors, which occurs via multiple mechanisms (e.g. AR amplification, AR mutation, de-regulation of AR co-activators, and/or activation by alternate pathways). Given the importance of AR activity for CaP growth, considerable effort is being undertaken to delineate the function and regulation of AR modulatory proteins. Through elucidation of AR action in both early and late stage tumors, it is hoped that therapeutic targets will emerge to permanently ablate AR function and thus prevent recurrence/relapse. We and others have shown that activation of SWI/SNF chromatin remodeling complex(es) is required for AR function. SWI/SNF represents a large class of chromatin remodeling complexes, wherein unique combinations of associated subunits are hypothesized to lend specificity to SWI/SNF action. Here, we demonstrate that a non-essential SWI/SNF subunit, BAF57, interacts directly with the AR and potently regulates both AR and AR co-activator function. This function of BAF57 not only governs AR transactivation potential, but also regulates androgen dependent proliferation in prostatic adenocarcinoma cells. Therefore, our studies support the hypothesis that BAF57 regulates AR activity through discrete mechanisms that could be targeted in CaP therapy. The studies proposed herein challenge this hypothesis by dissecting the mechanisms through which BAF57 controls AR activity (Aim 1), revealing specificity of the BAF57 requirement in CaP (Aim 2) and assessing the impact of BAF57 in the growth and progression of CaP in vivo (Aim 3). Together, these studies will reveal the efficacy of BAF57 as a therapeutic target in both early and late stage prostate cancer.