Deciphering Beta-Catenin Contributions in Prostate Cance

描述（由申请人提供）：前列腺癌（PrCa）是北美男性癌症相关死亡的第二大原因。在大多数情况下，PrCa变成雄激素非依赖性（Al）或激素难治性。Al - PrCa的进展是多因素的，可归因于循环生长因子激活促存活细胞信号，异常雄激素受体（AR）转录和逃避凋亡。我们已经证明，癌蛋白β -连环蛋白可以改变AR转录，并可能导致Al PrCa期间的异常生长。我们还发现肿瘤抑制因子PTEN可以负性调节β -catenin/Tcf信号。利用功能系统的损失和增益，我们建议进一步评估β -连环蛋白在PrCa中的作用。具体来说，前列腺特异性PTEN敲除小鼠将使我们能够评估β -连环蛋白的表达和分布以及调节其活性的已知分子。我们还将使用在可诱导的Tet调控启动子下稳定转染PTEN的LNCaP PrCa细胞。将评估这些细胞在异种移植肿瘤中的生长和PSA分泌情况。这些新颖的体内工具将有助于理解β -连环蛋白在Al PrCa中的作用。

DESCRIPTION (provided by applicant): Prostate cancer (PrCa) is the second leading cause of cancer related death in North American men. In the majority of cases, PrCa becomes androgen-independent (Al) or hormone refractory. Progression to Al PrCa is multi-factorial and can be attributed to activation of pro-survival cell signaling by circulating growth factors, aberrant androgen receptor (AR) transcription and evasion of apoptosis. We have shown that the oncoprotein, Beta-catenin, can alter AR transcription and potentially contribute towards aberrant growth during Al PrCa. We have also shown that the tumour suppressor, PTEN, can negatively regulate Beta-catenin/Tcf signaling. Using both loss and gain of function systems we proposed to further evaluate the role of Beta-catenin in PrCa. Specifically, a prostate specific PTEN knock-out mouse will allow us to evaluate expression and distribution of Beta-catenin and molecules known to regulate its activity. We will also employ the use of LNCaP PrCa cells stably transfected with PTEN under an inducible Tet regulated promoter. These cells will be assessed for growth and PSA secretion in tumors carried as xenografts. These novel in vivo tools will allow understanding to the role of Beta-catenin has in Al PrCa.