Protocadherin-PC and Prostate Cancer

原钙粘蛋白-PC 和前列腺癌

• 批准号: 7105762
• 负责人: Ralph Buttyan
• 金额: $ 5.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105762
• 关键词: behavior; genes; human; prostate; prostate neoplasms

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a major source of cancer morbidity and mortality in men. Androgen-deprivation, the main therapeutic intervention for advanced PCa patients, inevitably fails and the disease subsequently recurs in a hormone-refractory form that often leads to the death of the patient. Our goal of identifying novel molecular mechanisms through which PCa cells develop resistance to hormone therapy has led to the discovery of a unique gene product referred to as protocadherin-PC (PCDH-PC) that is upregulated in apoptosis- and hormone-resistant prostate cancer cells as well as in actual hormone-resistant tumors from patients. PCDH-PC is remarkable because of its male-specific nature (it is encoded on the human Y- chromosome) and because its expression is associated with activation of wnt- and Akt- signaling pathways as well as with the activation of a transdifferentiation process in which PCa cells acquire neuroendocrine (NE) cell-like characteristics. These behaviors (wnt-/Akt-signaling and NE phenotype) are found in advanced and hormone-resistant PCa cells and the work in this project will increase our understanding of PCDH-PC's role in hormone-resistant PCa. Experiments in Specific Aim 1 will explore the mechanism through which PCDH-PC upregulates wnt signaling by characterizing the domains of PCDH-PC that are involved in wnt signaling control. Experiments in Specific Aim 2 will characterize the effects of PCDH-PC expression on gene expression patterns in PCa cells and determine how PCDH-PC expression influences their malignant behavior. Work under Specific Aim 3 will develop a transgenic mouse model in which PCDH-PC expression is targeted to the prostate to determine whether expression of this gene product is sufficient to induce prostatic neoplasia or whether co-expression of this gene in existing transgenic prostate cancer models (LADY 12T-7 or PTEN knockout) leads to the development of more aggressive prostate cancers. By defining the mechanism through which PCDH-PC exerts its effects on the PCa cell and characterizing the malignant behaviors that are elicited by PCDH-PC expression, we will show the importance of this gene product for prostate cancer progression and better define it as a target for the development of therapeutics to control hormone-refractory disease.

描述（由申请人提供）：前列腺癌（PCA）是男性癌症发病率和死亡率的主要来源。雄激素剥夺是晚期PCA患者的主要治疗干预措施，不可避免地失败，随后疾病以激素难治性形式复发，通常导致患者死亡。我们确定PCA细胞通过对激素疗法产生抗性的新型分子机制的目标导致发现了一种独特的基因产物，称为protocadherin-PC（PCDH-PC），该产物在抗凋亡和抗激素和激素的前列腺癌细胞中被上调，并且在实际的激素癌细胞以及实际的激素癌中以及来自实际的激素剂量的患者中。 PCDH-PC由于其男性特异性性质（编码在人Y-染色体上）而引人注目，并且由于其表达与Wnt-和Akt-Signal传导途径的激活以及PCA细胞获得神经内分泌（NEEUROCORIRE（NEEROCORICE）类似细胞的特征的激活相关。这些行为（WNT-/AKT信号和NE表型）在耐激素和激素的PCA细胞中发现，该项目的工作将增加我们对PCDH-PC在耐激素耐药性PCA中的作用的理解。特定目标1中的实验将探索PCDH-PC通过表征与Wnt信号控制有关的PCDH-PC域上调WNT信号传导的机制。特定目标2中的实验将表征PCDH-PC表达对PCA细胞中基因表达模式的影响，并确定PCDH-PC表达如何影响其恶性行为。在特定目标3下的工作将开发一个转基因小鼠模型，其中PCDH-PC表达的目标是前列腺，以确定该基因产物的表达是否足以诱导前列腺肿瘤，还是在现有的转基因前列腺癌模型中对该基因的共表达（Lady 12t-7或Pten淘汰）（Lady 12t-7还是Pten敲门），导致更具攻击性的prestrostate Cancers cancers cancers cancersers的发展。通过定义PCDH-PC对PCA细胞的影响并表征PCDH-PC表达引起的恶性行为的机制，我们将展示该基因产物对前列腺癌进展的重要性，并更好地将其定义为用于控制激素差异疾病的疗法的目标。