Prostate cancer development and progression depend on androgen signaling through the androgen receptor (AR). Recent evidence indicates the continued presence of intratumoral dihydrotestosterone (DHT) during androgen deprivation therapy drives prostate cancer recurrence through the activation of AR. There are ongoing efforts to identify drugs that target AR and enzymes that catalyze the synthesis of testosterone and DHT. Temporary remediation of prostate cancer by surgical or medical castration or by the administration of an androgen biosynthetic inhibitor such as abiraterone acetate support a reliance on AR for prostate cancer growth. However, long term benefits have yet to be achieved. We identified 17β-hydroxysteroid dehydrogenase-6 (17β-HSD-6) as a major oxidative enzyme responsible for the conversion of androstanediol to DHT. The presence of 17β-HSD-6 at higher levels in normal prostate and prostate cancer cells than in other cell types suggests that the synthesis of DHT from androstanediol is a normal function of the prostate. Injection of androstanediol into castrated immunodeficient mice bearing the castration-recurrent CWR22 human prostate cancer xenograft demonstrated the capacity of prostate cancer cells to synthesize DHT from androstanediol. This so-called backdoor pathway contributes to the classical pathways of DHT synthesis to drive prostate cancer growth. Other factors that contribute to enhanced AR signaling and prostate cancer progression include increased levels of the melanoma antigen-A11 (MAGE-11) that binds the AR N-terminal FXXLF motif and increases AR stabilization and the response to low intratumoral levels of androgen. MAGE-11 functions synergistically with AR and coactivators to increase androgen-dependent gene regulation that drives prostate cancer growth. Longer term effectiveness of drugs that inhibit androgen biosynthesis may enhance the effects of therapies that target AR and its coregulators in the treatment of prostate cancer.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: Declaration of Funding: NIH.