The Role of the Androgen Receptor in the Development and Progression of Bladder Cancer

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642, USA.
Japanese Journal of Clinical Oncology (Impact Factor: 2.02). 05/2012; 42(7):569-77. DOI: 10.1093/jjco/hys072
Source: PubMed


Men are at a higher risk of developing bladder cancer than women. Since bladder cancer cell lines and tissues were found to express the androgen receptor, efforts have been made to inspect whether androgen-mediated androgen receptor signals are implicated in bladder carcinogenesis as well as cancer progression. Mounting evidence supports the view that bladder cancer is a member of the endocrine-related tumors and may clearly explain the gender-specific difference in the incidence. However, the underlying mechanisms of how androgen receptor signals regulate bladder cancer growth are still far from fully characterized. Moreover, it remains controversial whether the androgen receptor pathway always plays a dominant role in bladder cancer progression. In this review, we summarize the available data on the involvement of androgen receptor signaling in bladder cancer. In particular, current evidence demonstrating the stimulatory effects of androgens on tumor progression or, more convincingly, tumorigenesis via the androgen receptor pathway may offer great potential for androgen deprivation as a therapeutic or chemopreventive option in patients with bladder cancer.

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    • "The basis for the gender-related difference in incidence has not been precisely ascertained. Expression of the androgen receptor has been suggested to play a role not only in the development of the higher incidence of bladder cancer in males but also in determination of prognosis, although some conflicting results have been reported [reviewed in (19)]. It will be of interest to examine STAG2 mutation in relation to both gender and the status of androgen receptor and its targets. "
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    ABSTRACT: Inactivating mutations of STAG2 have been reported at low frequency in several cancers. In glioblastoma, the function of STAG2 has been related to maintenance of euploidy via its role in the cohesin complex. In a screen of a large series of bladder tumors and cell lines, we found inactivating mutations (nonsense, frameshift and splicing) in 67 of 307 tumors (21.8%) and 6 of 47 cell lines. Thirteen missense mutations of unknown significance were also identified. Inactivating mutation was associated with low tumor stage (p=0.001) and low grade (p=0.0002). There was also a relationship with female patient gender (p=0.042). Examination of copy number profiles revealed an inverse relationship of mutation with both fraction of genome altered and with whole chromosome copy number changes. Immunohistochemistry showed that in the majority of cases with inactivating mutations, STAG2 protein expression was absent. Strikingly we identified a relatively large sub-set of tumors (12%) with areas of both positive and negative immunoreactivity, in only 4 of which a potentially function-altering mutation was detected. Regions of differential expression were contiguous and showed similar morphological phenotype in all cases. Microdissected positive and negative areas from one tumor showed an inactivating mutation to be present only in the negative area, suggesting intra-tumoral sub-clonal genomic evolution. Our findings indicate that loss of STAG2 function plays a more important role in non-invasive than in muscle-invasive bladder cancer and suggest that cohesin complex-independent functions are likely to be important in these cases.
    Human Molecular Genetics 11/2013; 23(8). DOI:10.1093/hmg/ddt589 · 6.39 Impact Factor
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    • "It is important to note that CP-31398 showed dose-dependent suppression of invasive TCC inhibition in female mice, with the higher dose showing 100% inhibition of invasive TCC (Table W1). The mechanisms for the difference in SV40 T antigen–induced tumor progression in male versus female mice are not clear, but they may be due, in part, to the influence of sex hormones on tumor growth [35] [36]. Epidemiological data indicate that men also have a three to four times higher chance of developing bladder cancer compared with women; however, differences between men and women in the rate of tumor progression have not been studied extensively. "
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    ABSTRACT: The high prevalence of bladder cancer and its recurrence make it an important target for chemoprevention. About half of invasive urothelial tumors have mutations in p53. We determined the chemopreventive efficacy of a p53-stabilizing agent, CP-31398, in a transgenic UPII-SV40T mouse model of bladder transitional cell carcinoma (TCC) that strongly resembles human TCC. After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm of CP-31398 for 34 weeks. Progression of bladder cancer growth was monitored by magnetic resonance imaging. At 40 weeks of age, all mice were killed; urinary bladders were collected to determine weights, tumor incidence, and histopathology. There was a significant increase in bladder weights of transgenic versus wild-type mice (male: 140.2 mg vs 27.3 mg, P < .0001; female: 34.2 mg vs 14.8 mg, P < .0001). A significant decrease in the bladder tumor weights (by 68.6-80.2%, P < .0001 in males and by 36.9-55.3%, P < .0001 in females) was observed in CP-31398-treated mice. Invasive papillary TCC incidence was 100% in transgenic mice fed control diet. Both male and female mice exposed to CP-31398 showed inhibition of invasive TCC. CP-31398 (300 ppm) completely blocked invasion in female mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax, and Annexin V) with a decrease in vascular endothelial growth factor in transgenic mice fed CP-31398. These results suggest that p53-modulating agents can serve as potential chemopreventive agents for bladder TCC.
    Neoplasia (New York, N.Y.) 08/2013; 15(8):966-74. DOI:10.1593/neo.13704 · 4.25 Impact Factor
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    • "Unlike most epithelial tumors, divergent pathways of tumorigenesis are involved in urothelial carcinoma [2]. These separate mechanisms produce at least two distinct types of neoplasms: non-invasive, low-grade tumor and high-grade, often invasive, carcinoma [3]. Patients with low grade tumors usually undergo transurethral tumor resection (TUR). "
    Journal of Cancer Therapy 01/2013; 04(06):7-19. DOI:10.4236/jct.2013.46A3002
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