Role of NCoR in Antiandrogen Resistance in Prostate Cancer

NCoR 在前列腺癌抗雄激素抵抗中的作用

基本信息

批准号：
8018395
负责人：
IRINA AGOULNIK
金额：
$ 16.2万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-13 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018395
关键词：
Ablation Affect Aging Agonist Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Apoptosis Benign Prostatic Hypertrophy Bicalutamide Biology Cancer Model Cancer Patient Cause of Death Cell Proliferation Cells Chromatin Clinical Complex Data Development Disease Down-Regulation Epithelial Epithelium Exploratory/Developmental Grant Future Gene Targeting Genes Genetic Transcription Growth Histones Hormones Human Knockout Mice Laboratories Lead Ligands Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Mus Mutant Strains Mice NIH Program Announcements Neoplasms Nuclear Nuclear Receptors Organ PC3 cell line Pathway interactions Patients Phosphorylation Physical condensation Process Property Prostate Proteins Proto-Oncogene Proteins c-akt Receptor Signaling Recombinants Recruitment Activity Recurrent Malignant Neoplasm Refractory Resistance Role Sampling Screening procedure Structure of capsule of prostate Technology Testing Therapeutic Intervention Tissue Microarray Tissues Transgenic Mice alternative treatment androgen independent prostate cancer base cancer cell cell motility gene repression hormone refractory prostate cancer in vivo in vivo Model insight men mouse development mouse model new therapeutic target prevent probasin promoter public health relevance receptor function response steroid hormone receptor success tool transcription factor tumor progression tumorigenesis

项目摘要

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.

描述（由申请人提供）：激素难治性前列腺癌目前无法治愈，是前列腺癌患者死亡的主要原因，通常在雄激素消融治疗（一种拮抗雄激素受体（AR）转录活性的过程）后出现。 AR是一种核转录因子，其活性由其在AR调节基因的启动子上组装的共激活子和辅阻遏物决定。有大量数据证明 AR 共激活剂在前列腺癌中的重要性。之前我们表明 NCoR（核受体辅阻遏物）可抑制 AR 的激动剂和拮抗剂依赖性转录抑制。我们发现 AR 辅阻遏物 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，比卡鲁胺不会抑制前列腺癌细胞系的增殖和运动。使用 Affimetrix 微阵列，我们确定 LNCap 前列腺癌细胞中 NCoR 表达的缺失会显着影响 AR 下游靶标的表达，从而导致 AKT 和 PCDH11 途径的激活。使用人类前列腺组织微阵列，我们发现NCoR在人类前列腺中高表达，并且其表达在前列腺癌中显着降低。我们发现前列腺癌中 NCoR 的下调与 Akt 磷酸化的增加之间存在显着相关性。小鼠前列腺的发育严格依赖于雄激素，并且与人类前列腺一样，它表达高水平的 NCoR。我们的主要假设是，NCoR 的减少将导致前列腺上皮细胞增殖增加、雄激素独立，并最终导致类似于人类前列腺癌的恶性转化。具体来说，在本申请中，我们建议：1）检验NCoR对于正常前列腺上皮的更新和维持是必需的假设。我们将通过使用 Cre/loxP 重组技术创建具有前列腺中 NCoR 基因靶向消融的突变小鼠来测试这一假设。 2) 确定NCoR的前列腺特异性消融是否会导致恶性转化和AR信号传导增加。我们将确定前列腺对雄激素消融的反应是否需要 NCoR。这将通过比较正常小鼠和前列腺中 NCoR 耗尽的小鼠对雄激素消融的反应来实现。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。它将让我们了解不再表达 NCoR 的前列腺癌中 AR 对激动剂和拮抗剂的反应如何变化，从而提供新的治疗靶点。它还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表达，并将为未来筛选在NCoR不存在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：不依赖雄激素的复发性癌症目前无法治愈。我们发现 NCoR 蛋白是抗雄激素治疗成功所必需的。使用来自 400 多名患者的前列腺癌样本，我们发现与正常前列腺组织相比，前列腺癌中的 NCoR 水平显着降低。我们在此建议创建一个前列腺中缺乏 NCoR 的小鼠模型，以了解抗雄激素抵抗的机制。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疗法。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nuclear Receptor Corepressor 1 Expression and Output Declines with Prostate Cancer Progression.

核受体辅阻遏物 1 的表达和输出随着前列腺癌的进展而下降。

DOI：
发表时间：
2016-08-01
期刊：
影响因子：
0
作者：
Lopez, Sandra M;Agoulnik, Alexander I;Zhang, Manqi;Peterson, Leif E;Suarez, Egla;Gandarillas, Gregory A;Frolov, Anna;Li, Rile;Rajapakshe, Kimal;Coarfa, Christian;Ittmann, Michael M;Weigel, Nancy L;Agoulnik, Irina U
通讯作者：
Agoulnik, Irina U