Androgens, such as testosterone, are the primary male sex hormone; it has been extensively studied in male reproductive cancers such as prostate cancer.
From a therapeutic standpoint, androgen deprivation therapy is effective against prostate cancer, but its actions in bladder cancer are less robust, suggesting that androgens and other sex hormones exhibit tissue specific behavior. This is true for estrogens as well, the primary female sex hormone, functioning uniquely in bladder versus breast cancer.
Cumulative evidence from the last half century has correlated increased male bladder cancer risk to androgens and androgen receptors (AR) (1-3). Moreover, Miyamoto et al illustrated that androgens and AR function both independently and dependently to potentiate BC risk in males (4). Consistently, Chang and colleagues discovered that a certain membrane androgen receptor functions through a noncanonical AR pathway to promote bladder cancer (5). These studies suggest the complex interplay of pathways working to modulate tumor risk in males.
Identifying downstream targets is necessary to understand how exactly androgens and AR alter the biological landscape in males. Recently, we found that AR represses a known biomarker of cancer stem cells and driver of progressive disease in multiple tumor types—CD44 (6). While prior evidence has been somewhat contradicting, past studies have correlated high AR levels with lower staged tumors and visa versa (7-9). This suggests that AR may operate through the AR-CD44 axis to promote tumor initiation but suppress tumor progression, resulting in higher male BC incidence but more advanced disease in women.
Big questions remain: Are androgens and AR solely responsible for sex differences in BC development? Will targeting these pathways be therapeutically viable? Because BC diagnosis often occurs later in life (median diagnosis age 73)—an age with decreased sex hormone levels—sex hormones cannot be the sole driver of sex differences in BC. The BCGSP aims to refine our understanding on how androgens and AR, in conjunction with other major sex-biasing factors—sex chromosomes, epigenetic regulators, and immune cells—work together to increase male BC risk.
1) Bertram JS, Craig AW. Specific induction of bladder cancer in mice by butyl-(4-hydroxybutyl)-nitrosamine and the effects of hormonal modifications on the sex difference in response. European journal of cancer. 1972;8(6):587-94.
2) Laor E, Schiffman ZJ, Braunstein JD, Reid RE, Tolia BM, Koss LG, et al. Androgen receptors in bladder tumors. Urology. 1985;25(2):161-3.
3) Jing Y, Cui D, Guo W, Jiang J, Jiang B, Lu Y, et al. Activated androgen receptor promotes bladder cancer metastasis via Slug mediated epithelial-mesenchymal transition. Cancer Lett. 2014;348(1-2):135-45.
4) Miyamoto H, Yang Z, Chen YT, Ishiguro H, Uemura H, Kubota Y, et al. Promotion of bladder cancer development and progression by androgen receptor signals. Journal of the National Cancer Institute. 2007;99(7):558-68.
5) Chen J, Chou F, Yeh S, Ou Z, Shyr C, Huang C, et al. Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Galphai protein/MAPK/MMP9 intracellular signaling. Oncogene. 2019.
6) Sottnik JL, Vanderlinden L, Joshi M, Chauca-Diaz A, Owens C, Hansel DE, et al. Androgen Receptor Regulates CD44 Expression in Bladder Cancer. Cancer Res. 2021;81(11):2833-46.
7) Laor E, Schiffman ZJ, Braunstein JD, Reid RE, Tolia BM, Koss LG, et al. Androgen receptors in bladder tumors. Urology. 1985;25(2):161-3.
8) Li P, Chen J, Miyamoto H. Androgen Receptor Signaling in Bladder Cancer. Cancers (Basel). 2017 Feb 22;9(2):20. doi: 10.3390/cancers9020020. PMID: 28241422; PMCID: PMC5332943.
9) Mir C, Shariat SF, van der Kwast TH, Ashfaq R, Lotan Y, Evans A, et al. Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi-institutional study. BJU Int. 2011;108(1):24-30.