Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue.
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 5alpha-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 5alpha-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5alpha-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5alpha-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5alpha-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 5alpha-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5alpha-reductase inhibitors.
Department of Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, Los Angeles 90089-9075, USA.
Nick
N
Makridakis
Abebe
A
Akalu
Juergen K V
JK
Reichardt
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D019943:Amino Acid Substitution; D001483:Base Sequence; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011467:Prostate / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics*
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase