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Cell. 2013 Aug 29;154(5):1074-1084. doi: 10.1016/j.cell.2013.07.029.

A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
2
Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4
Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
5
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
6
Department of Urology, University of Washington School of Medicine, Seattle, WA 91809, USA.
7
Department of Urology, University of Washington School of Medicine, Seattle, WA 91809, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 91809, USA.
8
Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
9
Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
10
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Division of Hematology/Oncology, Department of Internal Medicine and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: sharifn@ccf.org.

Abstract

Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC.

PMID:
23993097
PMCID:
PMC3931012
DOI:
10.1016/j.cell.2013.07.029
[Indexed for MEDLINE]
Free PMC Article

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