Androgen receptor activation: a prospective therapeutic target for bladder cancer?

ABSTRACT

Introduction: Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies.

Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed.

Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

KEYWORDS:

• Androgen
• androgen receptor
• bladder
• carcinogenesis
• tumor progression
• urothelial cancer

Article highlights

• Androgen receptor (AR) is expressed in 13-78% of bladder urothelial carcinomas detected by immunohistochemistry.

• Androgen/AR promotes chemical carcinogen-induced urothelial carcinogenesis.

• AR signaling contributes to modulation of metabolism of bladder carcinogens.

• Androgen/AR promotes bladder cancer cell proliferation, cell migration/invasion, and angiogenesis.

• Androgen modulates various molecules as AR downstream targets, such as β-catenin, CD24, EGFR/ERBB2, and ELK1, each of which is known to play an important role in bladder cancer outgrowth.

• AR signaling and its related pathways have thus the potential of being chemopreventive and therapeutic targets for bladder cancer.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.