A Novel Mechanism for Control of Androgen Receptor Levels in HRPC

描述（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辅调节因子的控制，但内源性AR辅抑制因子下调AR水平的操作尚未在治疗上得到利用。我们已经证明，EBP 1，在我们的实验室中分离的蛋白质，其结合ErbB 3的能力，是一种AR辅阻遏物，抑制AR和AR靶基因的蛋白质水平，并抑制前列腺癌细胞的生长。EBP 1抑制AR功能的能力可以通过ErbB 3/4配体调蛋白（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ErbB 2/3异源二聚体可使内源性AR mRNA不稳定。我们假设EBP 1通过结合并以HRG诱导的方式破坏AR mRNA的稳定来介导HRG的作用。此外，我们推测，ErbB酪氨酸激酶抑制剂（TKI）的临床疗效令人失望，因为抑制ErbB活性的结果在废除HRG诱导的AR不稳定。我们的初步和已发表的数据表明，EBP 1调节前列腺癌细胞的生长，以响应HRG到TKI。这项资助将描述EBP 1影响前列腺癌细胞对TKI的敏感性的能力，以及EBP 1诱导的AR不稳定在这种反应中的作用。我们假设EBP 1可能是一种新的生物标志物，可用于识别可能受益于ErbB导向疗法的患者。特异性目的1的目的是阐明EBP 1使AR mRNA不稳定的机制。这些研究将a）确定EBP 1和AR mRNA在体内相互作用的区域及其功能意义B）确定EBP 1在介导HRG对AR mRNA的不稳定中的作用c）使用Ebp 1敲除小鼠模型确定在生理相关环境中EBP 1-AR mRNA相互作用的调节。特定目标II的目的是确定EBP 1状态是否影响前列腺癌细胞对TKI的反应能力。我们将使用体外和体内模型来确定操纵EBP 1水平或EBP 1突变是否可以改变细胞对TKI的反应。我们将检查所观察到的效应是否通过EBP 1诱导的AR不稳定来调节。

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.