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: 6652760
• 负责人: FRANK S FRENCH
• 金额: $ 20.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-26 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652760
• 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和前列腺癌（CAP）维持对雄激素的依赖性。 Cap在雄激素退出后经历了凋亡和回归，但最终在没有睾丸雄激素的情况下会出现。在雄性裸鼠中传播的人盖异种移植物（CWR22）保留了这些生物学特征，包括在没有睾丸雄激素的情况下cast割后的回归和生长后的复发。撤回雄激素刺激后，CWR22的AR水平降低。然而，相对于从cast割小鼠回归的CWR22，复发性CWR22肿瘤表达了高水平的AR。在复发的CWR22中，核免疫染色的强度增加与在没有雄激素的情况下AR激活一致。此外，在经常性的XWR22中，cwr22肿瘤减少的雄激素调节的mRNA被上调。这项研究的目的是确定AR和AR靶基因网络在CAP无关的生长中的作用。该项目的具体目的是：（1）描述控制AR mRNA和蛋白质稳态表达水平的机制，在c割和经常生长后CWR 22肿瘤中。表征复发性CWR22肿瘤中AR（蛋白质稳定性和磷酸化）的激活特性。 （2）鉴定CWR22中雄激素调节的基因，重点是AR刺激的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，重点是AR刺激的细胞生长的潜在介质。比较这些雄激素调节基因在cast骨小鼠中的表达水平。 （3）确定使用显性 - 阴性AR抑制AR抑制AR的反式激活和AR定向的核酶以防止AR表达的雄激素在复发的CWR22肿瘤中的雄激素非依赖性功能。 （4）阐明了控制雄激素调节基因在复发的CWR22（a）AR依赖性机制中表达的机制；或（b）非AR依赖机制。