Immunohistochemistry in tissue samples showed the expression

Immunohistochemistry in tissue samples showed the expression of several nuclear receptor co-activators, including NCOA1, NCOA2, NCOA3, CREBBP, and EP300, in 85–100% of sodium salt tumors even some of which lacked AR expression (Boorjian et al., 2009). Knockdown of each co-activator also resulted in significant reduction of the growth of AR-positive bladder cancer cells. However, inconsistent with the findings in prostate cancer, androgen treatment failed to up-regulate the expression of these co-activators in AR-positive bladder cancer cells (Boorjian et al., 2009). JMJD2A and LSD1 are newly discovered co-regulators that mediate AR transactivation via histone-lysine demethylation mechanisms. Immunohistochemistry in radical cystectomy specimens further showed strong correlations between AR levels and JMJD2A or LSD1 expression (Kauffman et al., 2011). Down-regulation of JMJD2A and up-regulation of LSD1 were seen in tumors, compared with benign urothelial tissues, and loss of JMJD2A was associated with lymphovascular invasion and worse overall survival. Remarkably, pharmacological inhibition of LSD1 results in significant decreases in the growth as well as androgen-induced AR transcription in bladder cancer cells (Kauffman et al., 2011). Nur77 is a ubiquitous orphan receptor that not only functions as a co-activator via forming a complex with SRC-1, a major steroid hormone receptor co-activator, but is also known to involve cell cycle mediation and apoptosis. Nur77 has been shown to compete with AR for binding to SRC-1 in bladder cancer cells, and its inactivation via a small molecule agonist results in the suppression of androgen-dependent cell growth (Wu et al., 2013a). It has been suggested, as described above, that β-catenin/Wnt signaling plays an important role in urothelial carcinogenesis as well as cancer progression (Jing et al., 2014, Kastritis et al., 2009, Li et al., 2013, Lin et al., 2013). Specifically, AR and β-catenin were shown to co-express at the nuclei of bladder cancer cells in the presence of androgens and form a complex with T-cell factor, a co-factor of β-catenin and a downstream component of Wnt signaling (Li et al., 2013). Thus, androgen-mediated AR signals appear to synergize with β-catenin in urothelial cancer cells and may thereby promote tumor growth.
Conclusion Current evidence indicates a critical role of androgen-mediated AR signals in the pathogenesis of urothelial cancer and supports that it is an endocrine-related neoplasm. Specifically, activation of AR and associated signaling pathways correlates with the promotion of urothelial cancer initiation and growth (Fig. 1), which helps explain the sex disparities, particularly male dominance in its incidence. It is also likely that AR signals are involved in resistance to chemotherapy for urothelial cancer. On the other hand, there are conflicting findings in surgical specimens as to the relationship between the status of AR expression in urothelial tumors and their histopathological characteristics or patient outcomes, some of which are inconsistent with those in laboratory-based studies. Thus, further mechanistic studies are required to determine the precise functional role of AR and related signals in the regulation of urothelial cancer outgrowth. Based on available preclinical data as well as those from retrospective clinical studies, AR inactivation is anticipated to be an effective chemopreventive or therapeutic approach for urothelial cancer. Thus, prospective cohort studies of anti-AR treatment in patients with urothelial cancer are encouraged. Indeed, a few early phase clinical trials (e.g.NCT02605863, NCT02788201, NCT02300610) are being conducted to assess the efficacy of AR inhibitors in patients with bladder cancer. Of note, androgen deprivation therapy has been widely used for the treatment of, for instance, prostate cancer, and numerous options are clinically available. It may therefore be able to be readily applied to any of these to urothelial cancer patients.