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HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer

Nature Reviews Urology volume 15, pages 191196 (2018) | Download Citation


Patients with advanced prostate cancer who receive androgen deprivation therapy (ADT) almost invariably develop castration-resistant disease. The mechanism of resistance is largely based on synthesis of intratumoral androgens from adrenal precursors, requiring enzymatic action of 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1 (3β-HSD1), encoded by HSD3B1. A nucleotide polymorphism (1245A>C) in HSD3B1 results in a protein variant with increased steady-state levels and subsequently increased androgen synthesis from extragonadal precursors. Multiple clinical studies have shown that patients with the variant allele have significantly worse outcomes after ADT than those without, indicating that HSD3B1 variant status is a predictive biomarker of shortened ADT response. In addition, inheritance of the HSD3B1 variant is associated with extended responses to 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition with a nonsteroidal agent, adding to evidence of increased tumour dependence on extragonadal androgens in patients who inherited the HSD3B1 variant. However, steroidal drugs with a 3β-hydroxyl, Δ5-structure, such as abiraterone, are also metabolized by 3β-HSD1, and 5α-abiraterone, a downstream metabolite, has been shown to activate the androgen receptor, potentially driving cancer progression. These data indicate a potential requirement to modify the treatment framework of patients harbouring variant HSD3B1.

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  1. 1.

    , & Androgen deprivation therapy for prostate cancer. JAMA 294, 238–244 (2005).

  2. 2.

    Minireview: Androgen metabolism in castration-resistant prostate cancer. Mol. Endocrinol. 27, 708–714 (2013).

  3. 3.

    et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J. Clin. Oncol. 26, 1148–1159 (2008).

  4. 4.

    et al. DHT concentrations in human prostate cancer tissue. J. Clin. Endocrinol. Metab. 46, 440–444 (1978).

  5. 5.

    , , , & Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin. Cancer Res. 11, 4653–4657 (2005).

  6. 6.

    et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 68, 4447–4454 (2008).

  7. 7.

    et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

  8. 8.

    et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

  9. 9.

    et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

  10. 10.

    et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

  11. 11.

    , & Androgen signaling in prostate cancer. Cold Spring Harb Perspect Med 7, a030452 (2017).

  12. 12.

    et al. Molecular biology of the 3β-hydroxysteroid dehydrogenase/Δ54 isomerase gene family. Endocr. Rev. 26, 525–582 (2005).

  13. 13.

    et al. A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer. Cell 154, 1074–1084 (2013).

  14. 14.

    et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 17, 1435–1444 (2016).

  15. 15.

    et al. Independent validation of effect of HSD3B1 genotype on response to androgen-deprivation therapy in prostate cancer. JAMA Oncol. 3, 856–857 (2017).

  16. 16.

    et al. Association of HSD3B1 genotype with response to androgen-deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer. JAMA Oncol. (2017).

  17. 17.

    et al. Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer. Nature 523, 347–351 (2015).

  18. 18.

    et al. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533, 547–551 (2016).

  19. 19.

    et al. Steroidogenic metabolism of galeterone reveals a diversity of biochemical activities. Cell Chem. Biol. 24, 825–832.e6 (2017).

  20. 20.

    et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N. Engl. J. Med. 377, 352–360 (2017).

  21. 21.

    et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N. Engl. J. Med. 377, 338–351 (2017).

  22. 22.

    et al. HSD3B1 and Response to a nonsteroidal CYP17A1 Inhibitor in castration-resistant prostate cancer. JAMA Oncol. (2017).

  23. 23.

    US National Library of Medicine. (2016).

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Author information


  1. Daniel Hettel is at the Lerner College of Medicine, Education Institute, and the Department of Cancer Biology, Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Daniel Hettel
  2. Nima Sharifi is at the Lerner College of Medicine, Education Institute, the Department of Cancer Biology, Lerner Research Institute, the Department of Urology, Glickman Urological and Kidney Institute, and the Department of Haematology and Oncology, Taussig Cancer Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, Ohio 44195, USA.

    • Nima Sharifi


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Both authors researched data for the article, made substantial contributions to discussion of its content, wrote, and reviewed and/or edited the manuscript before submission.

Competing interests

A patent application has been filed by the Cleveland Clinic for a method of steroid-dependent disease treatment based on HSD3B1. N.S. is listed as a co-inventor on this patent application.

Corresponding author

Correspondence to Nima Sharifi.

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