Recent advances in understanding the role of sex hormone receptors in urothelial cancer

Abstract

Sex hormones, including androgens and estrogens, are known to have widespread physiological actions beyond the reproductive system via binding to their cognitive receptors, members of the nuclear receptor superfamily that function as ligand-inducible transcription factors. Meanwhile, a growing body of evidence has indicated the involvement of androgen receptor, as well as estrogen receptors such as estrogen receptor-α and estrogen receptor-β, in the pathogenesis and growth of various types of malignancies, including urothelial cancer. Additionally, in bladder cancer, the activity of sex hormone receptors has been implicated in modulating sensitivity to conventional non-surgical therapy. These may clearly explain sex-related differences in the incidence and prognosis of bladder cancer. This article focuses on summarizing the recent progress on understanding the role of sex hormones and their receptors in urothelial tumorigenesis, urothelial cancer progression, and resistance to non-surgical therapy for bladder cancer. Specifically, potential downstream effectors of sex hormone receptors have been newly identified. Thus, most of previous and subsequent data have indicated that activation of the androgen receptor or estrogen receptor-β pathway is favorable for urothelial cancer, while conflicting data exist especially on estrogen receptor-α functions.

Keywords: Androgen receptor; Bladder cancer; Estrogen receptor; Urothelial cancer.

Figure 1. Androgen/estrogen-mediated signals, including potential downstream effectors, in non-neoplastic urothelial cells or urothelial cancer cells. Androgens or estrogens have been suggested to modulate tumorigenesis and tumor progression, as well as resistance to conventional non-surgical therapy for bladder cancer, through the ligand-mediated AR, ERα, and/or ERβ pathway(s) via up-regulating/activating (red) or down-regulating/inactivating (blue) the downstream targets listed. A, androgen; ARE, androgen response element; E, estrogen; ERE, estrogen response element; HSP, heat shock protein.