Role of NCoR in Antiandrogen Resistance in Prostate Cancer

描述（由申请人提供）：激素难治性前列腺癌目前是无法治愈的，是前列腺癌患者死亡的主要原因，通常在雄激素消融治疗后出现-雄激素受体（AR）转录活性拮抗的过程。AR是一种核转录因子，其活性取决于其在AR调控基因启动子上组装的共激活子和共抑制子。有大量数据表明AR共激活剂在前列腺癌中的重要性。之前我们发现核受体共抑制因子（NCoR）抑制AR的激动剂和拮抗剂依赖的转录抑制。我们发现AR共抑制因子NCoR对于前列腺癌细胞对抗雄激素比卡鲁胺的反应是必需的。在没有NCoR的情况下，比卡鲁胺不抑制前列腺癌细胞的增殖和运动。使用affmetrix微阵列，我们确定LNCap前列腺癌细胞中NCoR表达的缺失会显著影响AR下游靶点的表达，导致AKT和PCDH11通路的激活。利用人前列腺组织微阵列技术，我们发现NCoR在人前列腺中高表达，在前列腺癌中表达明显降低。我们发现前列腺癌中NCoR的下调与Akt磷酸化水平升高之间存在显著相关性。小鼠前列腺的发育严格依赖于雄激素，并且像人类前列腺一样，它表达高水平的NCoR。我们的主要假设是，NCoR的减少会导致前列腺上皮细胞增殖增加，雄激素不依赖性，最终导致类似于人类前列腺癌的恶性转化。具体来说，在这个应用中，我们提出：1)检验NCoR是正常前列腺上皮的更新和维持所必需的假设。我们将通过使用Cre/loxP重组技术创建靶向消融前列腺NCoR基因的突变小鼠来验证这一假设。2)确定前列腺特异性消融NCoR是否会导致恶性转化和AR信号的增加。我们将确定前列腺对雄激素消融术的反应是否需要NCoR。这将通过比较正常小鼠和前列腺中NCoR缺失的小鼠对雄激素消融的反应来完成。新的NCoR突变小鼠将代表激素难治性雄激素非依赖性前列腺癌的体内模型。这将使我们了解在不再表达NCoR的前列腺癌中，AR对激动剂和拮抗剂的反应是如何变化的，从而提供新的治疗靶点。这也将使我们能够确定抗雄激素的生长抑制特性是否依赖于NCoR的表达，并将为未来筛选在没有NCoR的情况下有效的抗雄激素化合物提供基础。公共卫生相关性：雄激素非依赖性复发性癌症目前是无法治愈的。我们发现NCoR蛋白是抗雄激素治疗成功所必需的。从400多名患者的前列腺癌样本中，我们发现与正常前列腺组织相比，前列腺癌中的NCoR水平显著降低。为了了解抗雄激素耐药的机制，我们建议建立前列腺缺乏NCoR的小鼠模型。这种转基因小鼠可用于寻找雄激素非依赖性前列腺癌的新治疗方法。

DESCRIPTION (provided by applicant): Hormone refractory prostate cancer is currently incurable and is a main cause of death among prostate cancer patients, often emerging after androgen ablation therapy - a process that antagonizes androgen receptor (AR) transcriptional activity. AR is a nuclear transcription factor whose activity is determined by the coactivators and corepressors it assembles on the promoters of AR regulated genes. There are abundant data that demonstrate the importance of AR coactivators in prostate cancer. Previously we showed that NCoR (nuclear receptor corepressor) represses agonist and antagonist dependent transcription repression of AR. We found that AR corepressor NCoR is necessary for the response of prostate cancer cells to antiandrogen bicalutamide. Prostate cancer cell line proliferation and motility was not repressed by the bicalutamide in the absence of NCoR. Using Affimetrix microarrays we determined that depletion of NCoR expression in LNCap prostate cancer cells dramatically affected the expression of downstream targets of AR, leading to activation of AKT and PCDH11 pathways. Using human prostate tissue microarrays we found that NCoR is highly expressed in human prostate and its expression is significantly reduced in prostate cancer. We found significant correlation between downregulation of NCoR in prostate cancer and increased phosphorylation of the Akt. The development of the mouse prostate is strictly androgen dependent and, like the human prostate, it expresses high levels of NCoR. Our main hypothesis is that reduction in NCoR will result in increased proliferation of the prostate epithelium cells, androgen independence, and ultimately in malignant transformation similar to human prostate cancer. Specifically in this application we propose to: 1) test the hypothesis that NCoR is required for turnover and maintenance of normal prostate epithelium. We will test this hypothesis by creating mutant mice with targeted ablation of the NCoR gene in prostate using Cre/loxP recombinant technology. 2) determine if prostate-specific ablation of NCoR will lead to malignant transformation and increased AR signaling. We will determine if NCoR is required for the prostate response to androgen ablation. This will be accomplished by comparing responses to androgen ablation of normal mice and mice that have NCoR depleted in their prostates. The new NCoR mutant mice will represent an in vivo model for hormone-refractory androgen independent prostate cancer. It will allow us to understand how AR response to agonists and antagonists changes in prostate cancers that no longer express NCoR providing novel therapeutic targets. It will also allow us to determine if growth inhibitory properties of anti-androgens are dependent on NCoR expression and will provide a basis for future screening of anti-androgen compounds efficient in the absence of NCoR. PUBLIC HEALTH RELEVANCE: Androgen-independent recurrent cancer is currently incurable. We found that NCoR protein is required for the success of anti-androgen treatment. Using prostate cancer samples from over 400 patients we discovered significant decrease in the level of NCoR in prostate cancers compared to normal prostate tissue. We propose here to create a mouse model that would lack NCoR in prostate in order to understand the mechanism of anti-androgen resistance. This transgenic mouse can be used to search for new treatments for androgen-independent prostate cancer.