Gender-specific differences in muscle-invasive bladder cancer: The concept of sex steroid sensitivity

Abstract

Purpose: To describe the role of sex steroid-dependent growth of muscle-invasive bladder cancer (MIBC) and the role of single-nucleotide polymorphisms (SNP) located on chromosome 8q24 as a molecular explanation for gender-specific differences in the incidence and outcome of MIBC. Methods: A detailed, non-systematic analysis was performed for articles and reviews investigating the role of sex steroids in the development and progression of MIBC between 2000 and 2012. Results: Localized MIBCs overexpress the androgen receptor (AR), whereas in lymph node-positive stages, loss of AR expression has been found. High-risk SNPs of genes on chromosome 8q24, that is, the rs2294008 of prostate stem cell antigen (PSCA) gene, have been linked with increased susceptibility for MIBC. The PSCA gene possesses an androgen-responsive element (ARE) in its promoter region. Recent studies suggest that loss of AR responsiveness to the PSCA promoter may result in the induction of an androgen-independent mechanism, that is, the insulin-like growth factor-binding protein 2 signalling pathway-a key event in the development of hormone-independent prostate cancer-and this may increase the metastatic potential. In females, it can be hypothesized that due to the altered androgen levels, these mechanisms may be initiated earlier during tumor progression in females and result in inferior survival compared to males. Conclusion: Muscle-invasive bladder cancer (MIBC) is a sex steroid-dependent tumor. AREs in the promoter region of high-risk genes may drive tumor progression and result in loss of androgen responsiveness, which eventually leads to the activation of androgen-independent processes forming the metastatic potential. The determination of the AR status in cystectomy specimens additionally offers new adjuvant approaches after cystectomy. © 2013 Springer-Verlag Berlin Heidelberg.