ANDROGEN RECEPTOR FUNCTION IN RECURRENT PROSTATE CANCER

复发性前列腺癌中的雄激素受体功能

• 批准号: 6344766
• 负责人: FRANK S FRENCH
• 金额: $ 27.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-18 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344766
• 关键词: androgen receptor; androgens; athymic mouse; gel mobility shift assay; gene expression; genetic regulation; genetic transcription; growth factor; hormone related neoplasm /cancer; human tissue; male; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplasm /cancer transplantation; neoplastic growth; prostate neoplasms; receptor expression; tissue /cell culture

Description: (Applicant's Description) The human prostate is androgen dependent and prostate cancer (CaP), maintains this dependence on androgens. CaP undergoes apoptosis and regression following androgen withdrawal but eventually recurs in the absence of testicular androgens. The human CaP xenograft (CWR22) propagated in male nude mice, retains these biological characteristics including regression following castration and recurrence of growth after several months in the absence of testicular androgen. Following the withdrawal of androgen stimulation, AR levels decrease in CWR22. However, recurrent CWR22 tumors express high levels of AR relative to the regressing CWR22 from castrated mice. In recurrent CWR22 the increased intensity of nuclear immunostaining is consistent with AR activation in the absence of androgen. Moreover, androgen-regulated mRNAs that decrease in CWR22 tumors following castration are up-regulated in the recurrent XWR22. The goal of this research is to establish the role of AR and the AR target gene network in the androgen-independent growth of CaP. Specific Aims of this project are to: (1) Delineate the mechanisms controlling steady state expression levels of AR mRNA and protein in CWR 22 tumors after castration and recurrent growth. Characterize the activation properties of AR (protein stability and phosphorylation) in recurrent CWR22 tumors. (2) Identify androgen-regulated genes in CWR22 with emphasis on potential mediators of AR-stimulated cell growth. Compare the levels of expression of these androgen-regulated genes in CWR22 with emphasis on potential mediators of AR-stimulated cell growth. Compare the levels of expression of these androgen- regulated genes in castrate mice. (3) Determine the androgen-independent function of AR in the recurrent CWR22 tumors using a dominant- negative AR to inhibit AR to inhibit AR transactivation and an AR- directed ribozyme to prevent AR expression. (4) Elucidate the mechanism controlling expression of androgen-regulated genes in the recurrent CWR22 (a) AR-dependent mechanism; or (b) non-AR dependent mechanism.

描述：（申请人的描述）人类前列腺是雄激素依赖性的，并且前列腺癌（CaP）维持了对雄激素的这种依赖性。 CaP 在雄激素撤退后经历细胞凋亡和消退，但最终在睾丸雄激素缺乏的情况下复发。在雄性裸鼠中繁殖的人CaP异种移植物（CWR22）保留了这些生物学特征，包括去势后的退化以及在缺乏睾丸雄激素的情况下几个月后生长的复发。雄激素刺激取消后，CWR22 中的 AR 水平下降。然而，相对于来自阉割小鼠的消退CWR22，复发性CWR22肿瘤表达高水平的AR。在复发性 CWR22 中，核免疫染色强度的增加与雄激素不存在时 AR 的激活一致。此外，去势后 CWR22 肿瘤中雄激素调节的 mRNA 减少，但在复发性 XWR22 肿瘤中却上调。本研究的目的是确定 AR 和 AR 靶基因网络在 CaP 的雄激素非依赖性生长中的作用。该项目的具体目标是： (1) 阐明控制 CWR 22 肿瘤去势和复发生长后 AR mRNA 和蛋白稳态表达水平的机制。表征复发性 CWR22 肿瘤中 AR 的激活特性（蛋白质稳定性和磷酸化）。 (2) 鉴定 CWR22 中雄激素调节基因，重点关注 AR 刺激细胞生长的潜在介质。比较 CWR22 中这些雄激素调节基因的表达水平，重点关注 AR 刺激细胞生长的潜在介质。比较去势小鼠中这些雄激素调节基因的表达水平。 (3)使用显性负性AR抑制AR以抑制AR反式激活和AR定向核酶以阻止AR表达，确定AR在复发性CWR22肿瘤中的雄激素独立功能。 (4) 阐明控制复发性CWR22中雄激素调节基因表达的机制 (a) AR依赖性机制；或 (b) 非 AR 依赖机制。