The role of the androgen receptor in the development and progression of bladder cancer
ABSTRACT 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.
- SourceAvailable from: Chinthalapally V Rao
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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  . 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. "
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 · 5.40 Impact Factor
Journal of Cancer Therapy 01/2013; 04(06):7-19. DOI:10.4236/jct.2013.46A3002
- "Unlike most epithelial tumors, divergent pathways of tumorigenesis are involved in urothelial carcinoma . These separate mechanisms produce at least two distinct types of neoplasms: non-invasive, low-grade tumor and high-grade, often invasive, carcinoma . Patients with low grade tumors usually undergo transurethral tumor resection (TUR). "
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ABSTRACT: Androgen receptor (AR) signals have been suggested to contribute to bladder tumorigenesis and cancer progression. Activation of epidermal growth factor receptor (EGFR) also leads to stimulation of bladder tumor growth. However, crosstalk between AR and EGFR pathways in bladder cancer remains uncharacterized. We have recently shown that androgens activate the EGFR pathway in bladder cancer cells. The purpose of this study was to investigate the effects of EGF on AR activity in bladder cancer. EGF increased AR transcriptional activity by 1.2-, 1.9- and 2.0-fold in UMUC3, 5637-AR and J82-AR cell lines, respectively, over mock treatment and a specific EGFR inhibitor, PD168393, antagonized the EGF effect. Combined treatment of EGF and dihydrotestosterone (DHT) further induced AR transactivation while an AR antagonist, hydroxyflutamide (HF), abolished the effect of not only DHT but also EGF. In growth assays, EGF alone/DHT alone/EGF+DHT increased cell numbers by 16/12/19%, 6/14/18% and 30/12/38% in UMUC3-control-shRNA, 5637-AR and J82-AR, respectively, whereas the effects of EGF were marginal or less significant in UMUC3-AR-shRNA (8%) or AR-negative 5637-V (<1%) and J82-V (17%) cells. HF treatment at least partially counteracted the EGF effect on the growth of AR-positive cells. Western blotting demonstrated that EGF, especially in the presence of DHT, upregulated the expression of the p160 coactivator TIF2 and HF again blocked this stimulation. Co-immunoprecipitation revealed the association between AR and estrogen receptor (ER)-β or Src in UMUC3 cells and stronger associations with EGF treatment, implying the involvement of the AR/ER/Src complex in EGF-increased AR transactivation and cell growth. Current results, thus, suggest that EGF promotes bladder cancer cell proliferation via modulation of AR signals. Taken together with our previous findings, crosstalk between EGFR and AR pathways can play an important role in the progression of bladder cancer.International Journal of Oncology 08/2012; 41(5):1587-92. DOI:10.3892/ijo.2012.1593 · 3.03 Impact Factor