Activation of ?-catenin signaling in androgen receptor-negative prostate cancer cells.

ABSTRACT: To study Wnt/?-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the ?-catenin-androgen receptor (AR) interaction.We carried out ?-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of ?-catenin-mediated transcription), and sequenced the ?-catenin gene in MDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down ?-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed ?-catenin and AR in 27 bone metastases of human CRPCs.?-Catenin nuclear accumulation and TOP-flash reporter activity were high in MDA prostate cancer 118b but not in MDA prostate cancer 2b or PC-3 cells. MDA prostate cancer 118a and MDA prostate cancer 118b cells carry a mutated ?-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA prostate cancer 118b cells with downregulated ?-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant ?-catenin. Finally, we found nuclear localization of ?-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher's exact test), suggesting that reduced AR expression enables Wnt/?-catenin signaling.We identified a previously unknown downstream target of ?-catenin, HAS2, in prostate cancer, and found that high ?-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone metastatic prostate cancer. These findings may guide physicians in managing these patients.

SUBMITTER: Wan X 

PROVIDER: S-EPMC3271798 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature