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Castration-resistant prostate cancer (PCa) almost invariably occurs after androgen deprivation therapy for metastatic disease and is driven in part by androgen synthesis within the tumor. 3β-hydroxysteroid dehydrogenase isoenzyme-1 catalyzes the conversion of adrenal precursor steroids into potent androgens essential for PCa progression. A common 1245 A→C missense-encoding single nucleotide polymorphism in HSD3B1 (rs1047303), the gene that encodes this enzyme, leads to a more stable protein that is resistant to degradation and thus increased production of potent androgens from adrenal precursors, facilitating castration-resistant PCa development. Consistent with this mechanism, this adrenal-permissive HSD3B1(1245C) genotype is associated with inferior outcomes after androgen deprivation therapy for advanced PCa, and increased sensitivity to pharmacologic blockade of adrenal precursors in metastatic disease. Herein, we review current knowledge of the mechanisms conferred by HSD3B1 genotype to alter androgen physiology and accelerate development of castration-resistant disease and its associations with clinical PCa outcomes. In light of its effect on steroid physiology, we also discuss its potential associations with non-PCa phenotypes.

HSD3B1 Genotypes Conferring Adrenal-Restrictive and Adrenal-Permissive Phenotypes in Prostate Cancer and Beyond