Activation of Beta-Catenin Signaling in Androgen Receptor-Negative Prostate Cancer Cells.

WAN X; LIU J; LU J; VASSILIKI T; YANG J; STARBUCK M; DIAO L; EFSTATHIOU E; VAZQUEZ E; TRANCOSO P; SANKAR M; NAVONE N

CLINICAL CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2012 vol. 18 p. 726 - 736

1078-0432

Purpose: To study Wnt/b-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the b-catenin?androgen receptor (AR) interaction. Experimental Design: We carried out b-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of b-catenin?mediated transcription), and sequenced the b-catenin gene inMDA prostate cancer 118a, MDA prostate cancer 118b, MDA prostate cancer 2b, and PC-3 prostate cancer cells. We knocked down b-catenin in AR-negative MDA prostate cancer 118b cells and carried out comparative gene-array analysis. We also immunohistochemically analyzed b-catenin and AR in 27 bone metastases of human CRPCs. Results: b-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 b-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) inMDAprostate cancer 118b cells with downregulated b-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 b-catenin. Finally, we found nuclear localization of b-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P¼0.056, Fisher?s exact test), suggesting that reduced AR expression enables Wnt/b-catenin signaling. Conclusion: We identified a previously unknown downstream target of b-catenin, HAS2, in prostate cancer, and found that high b-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.