4.4 Article

Androgen activates β-catenin signaling in bladder cancer cells

期刊

ENDOCRINE-RELATED CANCER
卷 20, 期 3, 页码 293-304

出版社

BIOSCIENTIFICA LTD
DOI: 10.1530/ERC-12-0328

关键词

androgen receptor; antiandrogen; bladder cancer; TCF/LEF; Wnt/beta-catenin

资金

  1. Department of Defense Prostate Cancer Research Program [W81XWH-09-1-0305]

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Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/beta-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and beta-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of beta-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and beta-catenin in bladder tumors (P=0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous beta-catenin expression (P=0.0276), nuclear beta-catenin expression (P=0.0802), and co-expression of nuclear AR and beta-catenin (P=0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on beta-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of beta-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of beta-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of beta-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgen-induced associations of AR with beta-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate beta-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of beta-catenin signaling possibly via formation of AR/beta-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach.

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