More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer

A gain-of-function stabilizing somatic mutation in 3 beta-hydroxysteroid dehydrogenase type 1 (3 beta HSD1, HSD3B1) was reported in castration-resistant prostate cancer. The A -> C nucleotide polymorphism replaced asparagine-367 with threonine (3 beta HSD1-N367T) as a homozygous somatic mutation in a subset of castration-resistant prostate cancers by loss of heterozygosity of the wild-type allele. Increased stability of 3 beta HSD1-N367T was associated with decreased ubiquitin-mediated degradation and higher levels of dihydrotestosterone (DHT). The studies suggest that genetic instability in castration-resistant prostate cancer favors the more stable 3 beta HSD1-N367T mutant that contributes to drug resistance. A somatic mutation in a steroid metabolic enzyme required for DHT synthesis provides further support for intratumoral androgen synthesis contributing to prostate cancer progression.