Journal Article

HSD3B1, prostate cancer mortality and modifiable outcomes

Abdshah, Alireza, McKay, Rana R., Freitas, Pedro F. S., Sharifi, Nima

2025

Overview

Androgen receptor stimulation by testosterone and dihydrotestosterone is crucial for prostate cancer progression. Despite the initial effectiveness of androgen deprivation therapy (ADT), castration-resistant prostate cancer eventually develops in most men. A common germline missense-encoding polymorphism in HSD3B1 increases extra-gonadal androgen biosynthesis from adrenal precursors owing to increased availability of the encoded enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) — hence, it is called the adrenal-permissive enzyme. This mechanism explains the more rapid progression to castration-resistant prostate cancer in men who inherit this allele than in men without it via sustained androgen receptor activation despite ADT. Multiple clinical studies, including data derived from prospective phase III studies, have linked adrenal-permissive allele inheritance to inferior clinical responses to ADT and increased mortality, but reversal is possible with upfront adrenal androgen blockade. The adrenal-permissive allele exhibits divergent frequencies across various groups worldwide, which could contribute to differences in clinical outcomes among these populations. Large-scale data from the Million Veteran Program have shown homozygous HSD3B1 adrenal-permissive allele inheritance to be an independent biomarker of prostate cancer-specific mortality. Together, these observations support the integration of HSD3B1 into germline testing and clinical trials as it might help to identify groups at increased likelihood of benefiting from early, intensified, AR-targeting interventions. Lastly, 3βHSD1 is a promising target for pharmacological inhibition, which enables new strategies for systemic prostate cancer therapy. A common germline missense-encoding polymorphism in HSD3B1 , called the adrenal-permissive allele, facilitates androgen synthesis from adrenal precursors via increased 3β-hydroxysteroid dehydrogenase 1 (3βHSD1). Here, the authors focus on mechanistic and clinical investigations of 3βHSD1 and the clinical consequences and potential utility of detecting adrenal-permissive allele inheritance.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4025/1752 / 692/4028/67/68 / Androgen Antagonists - therapeutic use / Androgens / Cancer / Dehydrogenases / Enzymes / Humans / Inheritances / Male / Medicine / Medicine & Public Health / Mortality / Multienzyme Complexes - genetics / Multienzyme Complexes - metabolism / Perspective / Polymorphism / Progesterone Reductase - genetics / Progesterone Reductase - metabolism / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - mortality / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - mortality / Steroid Isomerases - genetics / Steroid Isomerases - metabolism / Treatment Outcome / Urology