title: Androgen activates β-catenin signaling in bladder cancer cells.
abstract: Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/β-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and β-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of β-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and β-catenin in bladder tumors (P=0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous β-catenin expression (P=0.0276), nuclear β-catenin expression (P=0.0802), and co-expression of nuclear AR and β-catenin (P=0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on β-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of β-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of β-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of β-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgen-induced associations of AR with β-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate β-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of β-catenin signaling possibly via formation of AR/β-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach.
authors: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors: Yi
authors: Y
authors: Li
authors: Yichun
authors: Y
authors: Zheng
authors: Koji
authors: K
authors: Izumi
authors: Hitoshi
authors: H
authors: Ishiguro
authors: Bo
authors: B
authors: Ye
authors: Faqian
authors: F
authors: Li
authors: Hiroshi
authors: H
authors: Miyamoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000728:Androgens; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D051820:TCF Transcription Factors; D051176:beta Catenin; D015741:Metribolone
keywords: TCF/LEF; Wnt/β-catenin; androgen receptor; antiandrogen; bladder cancer