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BMX controls 3ßHSD1 and sex steroid biosynthesis in cancer.
Li, Xiuxiu; Berk, Michael; Goins, Christopher; Alyamani, Mohammad; Chung, Yoon-Mi; Wang, Chenyao; Patel, Monaben; Rathi, Nityam; Zhu, Ziqi; Willard, Belinda; Stauffer, Shaun; Klein, Eric; Sharifi, Nima.
Affiliation
  • Li X; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Berk M; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Goins C; Center for Therapeutics Discovery, Lerner Research Institute.
  • Alyamani M; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Chung YM; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Wang C; Department of Inflammation and Immunity, Lerner Research Institute.
  • Patel M; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Rathi N; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Zhu Z; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Willard B; Mass Spectrometry Core, Lerner Research Institute.
  • Stauffer S; Center for Therapeutics Discovery, Lerner Research Institute.
  • Klein E; Genitourinary Malignancies Research Center, Lerner Research Institute.
  • Sharifi N; Department of Urology, Glickman Urological and Kidney Institute, and.
J Clin Invest ; 133(2)2023 01 17.
Article in En | MEDLINE | ID: mdl-36647826
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. 3ß-hydroxysteroid dehydrogenase-1 (3ßHSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3ßHSD1 in driving CRPC. In postmenopausal women, 3ßHSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3ßHSD1 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 3ßHSD1 cellular activity and generation of Δ4, 3-keto-substrates of 5α-reductase and aromatase, including in patient tissues. BMX directly interacts with 3ßHSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3ßHSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: J Clin Invest Year: 2023 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prostatic Neoplasms / Prostatic Neoplasms, Castration-Resistant Type of study: Prognostic_studies Limits: Humans / Male Language: En Journal: J Clin Invest Year: 2023 Document type: Article Country of publication: United States