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.

睾酮和二氢睾酮刺激雄激素受体对前列腺癌进展至关重要。尽管雄激素剥夺疗法 （ADT） 最初有效，但大多数男性最终会发展为去势抵抗性前列腺癌。HSD3B1 中常见的种系错义编码多态性增加了来自肾上腺前体的性腺外雄激素生物合成，这是由于编码的酶 3β-羟基类固醇脱氢酶 1 （3βHSD1） 的可用性增加——因此，它被称为肾上腺允许酶。这种机制解释了尽管 ADT，但通过持续的雄激素受体激活，遗传该等位基因的男性比没有该等位基因的男性更快地发展为去势抵抗性前列腺癌。多项临床研究，包括来自前瞻性 III 期研究的数据，已将肾上腺允许等位基因遗传与对 ADT 的不良临床反应和死亡率增加联系起来，但前期肾上腺雄激素阻断有可能逆转。肾上腺允许等位基因在全球不同群体中表现出不同的频率，这可能导致这些人群之间临床结果的差异。来自百万退伍军人计划的大规模数据表明，纯合子 HSD3B1 肾上腺允许等位基因遗传是前列腺癌特异性死亡率的独立生物标志物。总之，这些观察结果支持将 HSD3B1 整合到种系检测和临床试验中，因为它可能有助于确定更有可能从早期、强化、AR 靶向干预中受益的群体。最后，3βHSD1 是一个很有前途的药物抑制靶点，这为全身性前列腺癌治疗提供了新的策略。