UBC Theses and Dissertations
Deciphering the role of beta-catenin in prostate cancer Mulholland, David J.
Prostate cancer (PrCa) is the second leading cause of cancer related mortality in North American men. Treatment of advanced human PrCa occurs by way of hormone ablation therapy promoting an initial regression of tumour size and serum PSA levels. However, following androgen ablation is the inevitable occurrence of androgen independence (AI) and the lethal phenotype of metastasis. While the oncogenic Wnt/β-catenin/Tcf signaling axis is well correlated with colon cancer, increasing evidence suggests that β-catenin is also a contributor to progression of PrCa. β-catenin binds AR, in a ligand sensitive manner, to alter AR ligand specificity thereby promoting its response to non-gonadal ligands including androstenedione and estradiol. This thesis puts forth new knowledge regarding the functional interactions between AR, Wnt/β-catenin/Tcf and P13K/Akt signaling. Specifically, Wnt3a promotes ligand independent AR/β-catenin interactions, AR transactivation, PSA production and enhanced PrCa cell proliferation (Chapter 2). Upon exposure to androgens, AR and β-catenin undergo ligand dependent, nuclear co-translocation and formation of AR/β-catenin nuclear complexing. In the presence of androgens, β-catenin and AR complex at regulatory sites for AR transcription, thereby conferring the ability of β-catenin to function as an AR co-activator (Chapter 3). Upon androgen activation, a limited pool of β-catenin yields augmented AR signaling but diminished β-catenin/Tcf signaling. Functionally, this is achieved by way of a competitive balance of nuclear β-catenin between AR and Tcf transcriptional sites (Chapter 4). Accordingly, cells that are highly β-catenin/Tcf dependent demonstrate reduced cyclin DI activity, altered cell cycle and reduced cell proliferation. PTEN expression serves as a critical check-point in PrCa advancement, as a potent regulator both of β-catenin/Tcf function and, therefore, AR function. In vitro, PTEN regulates these effectors via GSK3β and ILK, two kinases with critical regulatory functions in PBK/Akt dependent cancers (Chapter 5). In vivo, gain-offunction (stable, inducible PTEN PrCa cells) and loss-of-function (PTEN -/- mouse model) analysis support that PTEN serves to regulate nuclear localization of β-catenin. Human tissue microarray analysis indicates that increased β-catenin expression is not only associated with increasing Gleason grade assignment and mitotic index but also with benign prostate pathologies (Chapter 6). These data indicate a dynamic and functional role for β-catenin in PrCa systems.