BMX controls 3HSD1 and sex steroid biosynthesis in cancer

Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3 beta-hydroxysteroid dehydrogenase-1 (3 beta HSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3 beta HSD1 in driving CRPC. In postmenopausal women, 3 beta HSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3 beta HSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3 beta HSD1 cellular activity and generation of Delta 4, 3-keto-substrates of 5 alpha-reductase and aromatase, including in patient tissues. BMX directly interacts with 3 beta HSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3 beta HSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.