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Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue

Oncogene volume 23, pages 7399–7405 (2004)Cite this article

Abstract

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5α-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5α-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5α-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5α-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5α-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5α-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5α-reductase inhibitors.

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Abbreviations

DHT:

dihydrotestosterone

LOH:

loss of heterozygosity

PCR:

polymerase chain reaction

SNP:

single nucleotide polymorphism

SRD5A2:

steroid 5α-reductase type II locus

SSCP:

single-strand conformation polymorphism

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Acknowledgements

We thank Janice Daniel-Mejia (USC) for operating the automated ABI377 DNA sequencer and Claudia Weihe (USC) for helpful comments. This study was supported by DoD Grant PC 992018 (Project A to JKVR). We thank Ron Ross (USC) for helpful comments.

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Author notes

  1. Abebe Akalu

    Present address: Division of Radiation Oncology, New York University School of Medicine, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology and Institute for Genetic Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, 90089-9075, CA, USA

    Nick Makridakis, Abebe Akalu & Juergen K V Reichardt

  2. Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, 90089-9075, CA, USA

    Juergen K V Reichardt

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  1. Nick Makridakis
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  2. Abebe Akalu
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Correspondence to Juergen K V Reichardt.

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Makridakis, N., Akalu, A. & Reichardt, J. Identification and characterization of somatic steroid 5α-reductase (SRD5A2) mutations in human prostate cancer tissue. Oncogene 23, 7399–7405 (2004). https://doi.org/10.1038/sj.onc.1207922

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