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  • Review Article
  • Published:

Androgen synthesis in prostate cancer: do all roads lead to Rome?

Nature Reviews Urology volume 14, pages 49–58 (2017)Cite this article

Subjects

Key Points

  • Prostate cancers are capable of intratumoural androgen biosynthesis, which is a potential mechanism of castration resistance

  • Three possible competing androgen biosynthesis pathways exist, all of which might enable androgen biosynthesis in the presence of androgen-deprivation therapy

  • Currently, investigations of androgen biosynthesis rely heavily on preclinical models, which generally do not accurately reflect human disease in this setting

  • Identifying the dominant androgen biosynthetic pathway in each patient could have implications for treatment-related decisions

Abstract

The accumulation of high concentrations of signalling androgens within prostate tumours that progress despite use of androgen-deprivation therapy is a clinically important mechanism of the development of castration-resistant prostate cancer. In the past 5 years, data from a number of studies have increased our understanding of the enzymes and substrates involved in intratumoural androgen biosynthesis, and have implicated three competing pathways, which are likely to account for these observations. These pathways ('canonical', 'backdoor' and '5α-dione'), which can all ultimately generate the potent signalling androgen, dihydrotestosterone, involve many of the same enzymes, but differ in terms of substrate preference, reaction sequence and the organs and tissues in which they occur. For this reason, the relative importance of each pathway to the development and progression of prostate cancer remains controversial. In this Review, we describe the current understanding of androgen synthesis and the evidence for its role in castration resistance, and examine the evidence supporting and or rebutting the relevance of each pathway to patients with prostate cancer.

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Figure 1: Recognized androgen biosynthesis pathways.

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Acknowledgements

The Australian Prostate Cancer Centre Epworth is supported by the Australian Government as represented by the Department of Health and Ageing. N.M.C. is supported by a David Bickart Clinician Research Fellowship from the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne.

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Authors and Affiliations

  1. Australian Prostate Cancer Research Centre Epworth, Epworth Hospital, 89 Bridge Road, Richmond, 3121, Victoria, Australia

    Ryan Stuchbery, Christopher M. Hovens & Niall M. Corcoran

  2. Department of Surgery, Royal Melbourne Hospital, 300 Grattan Street, Parkville, 3050, Victoria, Australia

    Patrick J. McCoy, Christopher M. Hovens & Niall M. Corcoran

  3. Department of Urology, Royal Melbourne Hospital, 300 Grattan Street, Parkville, 3050, Victoria, Australia

    Christopher M. Hovens & Niall M. Corcoran

  4. Department of Urology, Frankston Hospital, 2 Hastings Road, Frankston, 3199, Victoria, Australia

    Niall M. Corcoran

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R.S. and P.J.M. researched data for this article, all authors made a substantial contribution to discussions of content, R.S. and N.M.C. wrote the manuscript and N.M.C. and C.M.H. reviewed and/or edited the manuscript before submission.

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Correspondence to Niall M. Corcoran.

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Stuchbery, R., McCoy, P., Hovens, C. et al. Androgen synthesis in prostate cancer: do all roads lead to Rome?. Nat Rev Urol 14, 49–58 (2017). https://doi.org/10.1038/nrurol.2016.221

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