Racial differences in androgen metabolism and receptor signaling in prostate cancer

Dihydrotestosterone (DHT) and testosterone (T) mediated androgen receptor (AR) nuclear translocation initiates transcription of AR target genes that are pivotal for prostate cancer (PrCa) development and progression. Here we provide data indicating that in contrast to European American (EA) men, African American (AA) men with localized PrCa can exploit an alternative progesterone-androsterone-5α-androstanedione pathway for DHT biosynthesis. Enzymes that are involved in alternate pathways of DHT biosynthesis are elevated in PrCa tissues from AA men, compared to EA men, and also correlated with increased serum DHT levels. In addition, higher serum DHT levels reflect increased RNA expression of AR target genes in PrCa tissues from AA men. Interestingly, serum T but not DHT levels are significantly lower in AA men compared to EA men with PrCa. Furthermore, serum progesterone and related intermediate metabolites levels that are produced during alternate pathways of DHT biosynthesis are significantly lower in AA men with PrCa and associated with a shorter time to disease progression. These data highlight that androgen biosynthesis is altered in therapy naïve localized PrCa in AA men, and can potentially serve as prognostic indicators of disease progression. Significance Our work provides a rationale to examine potential pharmacological interventions that target androgen biosynthesis and AR signaling earlier in the disease continuum in AA men with PrCa. Additionally, our study lays the groundwork for developing serum measurements of intermediate androgen metabolites as PrCa prognostic biomarkers.