Role of BAF57 in AR control and prostate cancer growth

BAF57 在 AR 控制和前列腺癌生长中的作用

• 批准号: 7618188
• 负责人: KAREN E KNUDSEN
• 金额: $ 26.63万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-04-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618188
• 关键词: Ablation; Activator Appliances; Adenocarcinoma Cell; Advanced Malignant Neoplasm; Alleles; Androgen Receptor; Androgens; Attenuated; Binding; Biological; Cancer Etiology; Cell Proliferation; Cells; Cessation of life; Chromatin Remodeling Factor; Clinical; Complex; Data; Diagnostic Neoplasm Staging; Event; Genetic Transcription; Growth; Ligands; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Menin; Modeling; Molecular; Mutation; Nucleosomes; Pathway interactions; Prostate; Prostate Adenocarcinoma; Proteins; Receptor Aggregation; Receptor Inhibition; Recruitment Activity; Recurrence; Recurrent tumor; Refractory; Regulation; Relapse; Role; Series; Signal Transduction; Specificity; Staging; Therapeutic; Therapeutic Intervention; Transactivation; Transcriptional Regulation; Tumor stage; Tumor-Derived; United States; Variant; effective therapy; human SMARCE1 protein; in vivo; men; prevent; promoter; receptor function; response; therapeutic target; therapy resistant; tumor; tumor progression

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.

描述（由申请人提供）：前列腺癌（CAP）是美国男性癌症死亡的第二大原因，因为对高级癌症的有效疗法仍然难以捉摸。传播的前列腺腺癌最初取决于雄激素的生长和生存。因此，这种肿瘤类型的治疗的支柱是通过直接抑制或通过抑制雄激素合成来消融雄激素受体（AR）功能。尽管这些治疗方法最初是有效的，但反复发作的肿瘤最终会出现对雄激素消融和AR抑制作用的难治。临床证据强烈支持以下概念：AR在这些复发性肿瘤中不当重新激活，该肿瘤通过多种机制（例如AR扩增，AR突变，AR共激活剂的下调和/或通过替代途径激活）发生的概念）。鉴于AR活性对CAP生长的重要性，正在努力描述AR调节蛋白的功能和调节。通过在早期和晚期肿瘤中阐明AR作用，希望治疗靶标将出现以永久消除AR功能，从而防止复发/复发。我们和其他人表明，AR功能需要SWI/SNF染色质重塑复合物（ES）的激活。 SWI/SNF代表了一类大量的染色质重塑络合物，其中假设相关亚基的独特组合以对SWI/SNF作用具有特异性。在这里，我们证明了一个非必需的SWI/SNF亚基BAF57直接与AR相互作用，并有效调节AR和AR共激活因子函数。 BAF57的这种功能不仅控制AR反式激活潜力，而且还调节前列腺腺癌细胞中雄激素依赖性增殖。因此，我们的研究支持以下假设，即BAF57通过可以针对CAP治疗的离散机制来调节AR活性。本文提出的研究通过解剖BAF57控制AR活性的机制来挑战这一假设（AIM 1），揭示了CAP中BAF57要求的特异性（AIM 2）（AIM 2）并评估BAF57在体内CAP增长和进展中的影响（AIM 3）。总之，这些研究将揭示BAF57作为治疗靶标在早期和晚期前列腺癌中的功效。