More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer

transcriptional activity, depends on a series of metabolic enzymes that catalyze the oxidation and reduction of steroid precursors from the adrenal gland or from cholesterol. A recent study by Chang et al.6 provides evidence that a gain-of-function 3βHSD1 somatic mutation contributes to prostate cancer progression by conferring resistance to proteasome-mediated degradation. 3βHSD1, like its other family member 3βHSD2, is an intracellular membrane-bound steroid metabolic enzyme with dual functions: Oxidization of the 3β-hydroxyl to 3-keto of 5α-configured steroids, and isomerization of the Δ5 carbon-carbon double bond to Δ4. 3βHSD1 and 3βHSD2 utilize NAD+ cofactors to catalyze four irreversible oxidative hydroxysteroid reactions in the pathway toward DHT synthesis: Conversion of pregnenolone to progesterone, conversion of 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, conversion of dehydroepiandrosterone (DHEA) to Δ4-androstenedione, and conversion of Δ5-androstenediol to testosterone. Both 3βHSDs are essential enzymes in the de novo synthesis of DHT. 3βHSD1 contributes to androgen metabolism primarily in peripheral tissues such as prostate, and 3βHSD2 is expressed predominantly in the adrenal gland and testis. One pathway of DHT synthesis that is independent of testosterone synthesis in castration-resistant prostate cancer is the conversion of adrenal-derived DHEA by 3βHSD1 to Δ4-androstenedione, which is converted by 5α-reductase to 5α-androstanedione, and then by 17β-HSD to form DHT.7 The gain-of-function 3βHSD1-N367T mutant described by Chang et al. extends the half-life of 3βHSD1 and is associated with increased synthesis of DHT from DHEA. Th e studies suggest that a somatic mutation in a steroid metabolic A gain-of-function stabilizing somatic mutation in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1, HSD3B1) was reported in castration-resistant prostate cancer. The A→C nucleotide polymorphism replaced asparagine-367 with threonine (3βHSD1-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 3βHSD1-N367T w a s a s s o c i a t e d w i t h d e c r e a s e d ubiquitin-mediated degradation and higher levels of dihydrotestosterone (DHT). Th e studies suggest that genetic instability in castration-resistant prostate cancer favors the more stable 3βHSD1-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. It has been known for >60 years that growth of prostate cancer depends on testicular androgen. Prostate cancers undergo remission for 1–2 years following androgen deprivation therapy, but recur in the absence of testicular androgen. Recurrence of prostate cancer growth during androgen deprivation therapy by medical castration using luteinizing hormone releasing hormone (LHRH) agonists has been attributed to increased expression of the androgen receptor (AR) and its coregulators, and to intratumoral androgen biosynthesis.1-5 Synthesis of DHT, the most potent androgen that activates AR INVITED RESEARCH HIGHLIGHT