Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Abstract

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

Impact of Androgen Suppression Therapy on the Risk and Prognosis of Bladder Cancer: A Systematic Review and Meta-Analysis

“…Bladder cancer (BCa), predominantly urothelial carcinoma, is a common malignant genitourinary tumor (1,2). Men are 3 to 4 times more frequently diagnosed with bladder cancer than women; however, women tend to be diagnosed with more advanced disease at presentation and have less favorable outcomes after treatment (1,(3)(4)(5). Female patients with urothelial carcinoma of the bladder have been shown to have worse cancer specific survival, overall survival and recurrencefree survival (5,6).…”

Androgen Receptor Signaling Induces Cisplatin Resistance via Down-Regulating GULP1 Expression in Bladder Cancer

“…Although resistance to CDDP-based chemotherapy is not uncommonly seen in patients with urothelial cancer, its underlying mechanisms are not fully understood. Meanwhile, AR activation in bladder cancer cells has been implicated to be associated with chemoresistance [ 12 , 13 , 14 , 15 , 21 , 22 , 23 , 24 ]. In the present study, we further investigated the role of GULP1, as a downstream target of AR, in CDDP resistance, using bladder cancer cell lines as well as surgical specimens.…”

“…The levels of AR expression should therefore be elevated in high-grade/muscle-invasive bladder cancers compared with low-grade/non-muscle-invasive tumors. However, conflicting data exist regarding the expression of AR mRNA [ 19 , 37 ] and protein (as reviewed in [ 11 , 12 ]) in different grades/stages of bladder tumors. Specifically, in a meta-analysis of immunohistochemical studies, AR expression was shown to be rather significantly down-regulated in high-grade or muscle-invasive tumors [ 38 ].…”

“…Meanwhile, androgen receptor (AR) signaling has been implicated in the induction of urothelial tumorigenesis [ 11 ], which may clearly explain the male dominance in the incidence of bladder cancer. More interestingly, AR activation has been linked to resistance to conventional non-surgical treatments for bladder cancer [ 12 ], including CDDP therapy [ 13 , 14 , 15 ], as well as intravesical bacillus Calmette-Guѐrin immunotherapy [ 16 ] and radiotherapy [ 17 ]. Nonetheless, it needs to be further elucidated how androgen-mediated AR signals control chemosensitivity in urothelial cancer.…”

Development of Mitomycin C-Loaded Nanoparticles Prepared Using the Micellar Assembly Driven by the Combined Effect of Hydrogen Bonding and π–π Stacking and Its Therapeutic Application in Bladder Cancer

“…Approximately 90% of bladder cancer is superficial growth, having the characteristics of polycentricity, easy recurrence, and metastasis and, unfortunately, the five-year survival rate of patients with stage IV bladder cancer is only 15% [3]. Presently, the clinical treatment of bladder cancer is mainly surgery, supplemented by radiotherapy and chemotherapy, but there is no ideal targeted therapy [4,5].…”