A Novel Mechanism for Control of Androgen Receptor Levels in HRPC

描述（由申请人提供）：雄激素受体（AR）对前列腺癌的发生和生长以及对激素的治疗反应至关重要。虽然AR的表达和活性受AR共调节因子的控制，但操纵内源性AR共抑制因子下调AR水平尚未被用于治疗。我们已经证明EBP1是我们实验室通过其结合ErbB3的能力分离出来的蛋白，是一种AR辅助抑制因子，可以抑制AR和AR靶基因的蛋白水平，抑制前列腺癌细胞的生长。EBP1抑制AR功能的能力可由ErbB3/4配体heregulin （HRG）调节，HRG是前列腺癌细胞生长的重要调节剂。最近来自独立实验室的研究表明，HRG激活ErbB2/3异源二聚体可以破坏内源性AR mRNA的稳定性。我们假设EBP1以HRG诱导的方式结合并破坏AR mRNA的稳定，从而介导HRG的作用。此外，我们假设ErbB酪氨酸激酶抑制剂（TKIs）的临床疗效令人失望，因为抑制ErbB活性可以消除hrg诱导的AR不稳定。我们的初步和已发表的数据表明，EBP1在HRG对TKIs的反应中调节前列腺癌细胞的生长。这项资助将描述EBP1影响前列腺癌细胞对TKIs敏感性的能力，以及EBP1诱导的AR不稳定在这种反应中所起的作用。我们假设EBP1可能是一种新的生物标志物，可用于识别可能受益于ErbB定向治疗的患者。特异性目的1的目的是阐明EBP1破坏AR mRNA稳定的机制。这些研究将a)确定EBP1与AR mRNA在体内相互作用的区域及其功能意义b)确定EBP1在介导HRG对AR mRNA失稳中的作用c)利用EBP1敲除小鼠模型确定生理相关环境下EBP1-AR mRNA相互作用的调节。Specific Aim II的目的是确定EBP1状态是否影响前列腺癌细胞对TKIs的反应能力。我们将使用体外和体内模型来确定EBP1水平的操纵或EBP1突变是否可以改变细胞对TKIs的反应。我们将检验观察到的效应是否通过ebp1诱导的AR不稳定调节。

DESCRIPTION (provided by applicant): The androgen receptor (AR) is central to the initiation and growth of prostate cancer and to the therapeutic response to hormones. Although the expression and activity of AR is controlled by AR coregulators, the manipulation of endogenous AR corepressors to downregulate AR levels has not been exploited therapeutically. We have demonstrated that EBP1, a protein isolated in our laboratory by its ability to bind ErbB3, is an AR corepressor that suppresses protein levels of AR and AR target genes and inhibits growth of prostate cancer cells. The ability of EBP1 to repress AR function can be regulated by the ErbB3/4 ligand heregulin (HRG) an important modulator of prostate cancer cell growth. Recent work from independent laboratories has shown that activation of the ErbB2/3 heterodimer by HRG can destabilize endogenous AR mRNA. We hypothesize that EBP1 mediates the effects of HRG by binding to and destabilizing AR mRNA in an HRG-inducible manner. Further, we postulate that the clinical efficacy of ErbB tyrosine kinase inhibitors (TKIs) has been disappointing because inhibition of ErbB activity results in abrogation of HRG-induced AR destabilization. Our preliminary and published data indicate that EBP1 modulates the growth of prostate cancer cells in response to HRG to TKIs. This grant will delineate the ability of EBP1 to affect the sensitivity of prostate cancer cells to TKIs and the role that EBP1-induced destabilization of AR plays in this response. We hypothesize that EBP1 may be a novel biomarker that can be used to identify patients that may benefit from ErbB directed therapies. The purpose of Specific Aim 1 is to elucidate the mechanism of the destabilization of AR mRNA by EBP1. These studies will a) determine the regions of interaction between EBP1 and AR mRNA in vivo and their functional significance b) determine the role of EBP1 in mediating HRG's destabilization of AR mRNA c) determine the regulation of EBP1-AR mRNA interactions in a physiological relevant setting using the Ebp1 knock out mouse model. The purpose of Specific Aim II is to determine if EBP1 status affects the ability of prostate cancer cells to respond to TKIs. We will use both in vitro and in vivo models to determine if manipulation of EBP1 levels or mutation of EBP1 can alter cellular response to TKIs. We will examine if the observed effects are regulated via EBP1-induced AR destabilization. PUBLIC HEALTH RELEVANCE: Hormone refractory prostate cancer is a uniformly fatal disease with a short survival time. The androgen receptor (AR) controls the growth of hormone refractory prostate cancer. This study will examine the ability of a novel AR corepressor (EBP1) to control levels of AR mRNA and ultimately prostate cancer growth.