Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention.
Inhibitors of 5alpha-reductase (SRD5A) that lower intraprostatic levels of dihydrotestosterone (DHT) reduce the overall incidence of prostate cancer (PCa), but there is significant variation in chemopreventive activity between individual men. In seeking molecular alterations that might underlie this variation, we compared gene expression patterns in patients with localized PCa who were randomized to prostatectomy alone versus treatment with two different doses of the SRD5A inhibitor dutasteride. Prostatic levels of DHT were decreased by >90% in both dutasteride-treated patient groups versus the untreated patient group. Despite significant and uniform suppression of tissue DHT, unsupervised clustering based on prostatic gene expression did not discriminate these groups. However, subjects could be resolved into distinct cohorts characterized by high or low expression of genes regulated by the androgen receptor (AR), based solely on AR transcript expression. The higher-dose dutasteride treatment group was found to include significantly fewer cancers with TMPRSS2-ERG genetic fusions. Dutasteride treatment was associated with highly variable alterations in benign epithelial gene expression. Segregating subjects based on expression of AR and androgen-regulated genes revealed that patients are differentially sensitive to SRD5A inhibition. Our findings suggest that AR levels may predict the chemopreventive efficacy of SRD5A inhibitors.
Mostaghel
Elahe A
EA
Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-100, Seattle, WA 91809, USA. emostagh@fhcrc.org
Geng
Linda
L
Holcomb
Ilona
I
Coleman
Ilsa M
IM
Lucas
Jared
J
True
Lawrence D
LD
Nelson
Peter S
PS
D058891:5-alpha Reductase Inhibitors; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000097:blood / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D001378:Azasteroids / Q000494:pharmacology; D000068538:Dutasteride; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D046888:Tissue Array Analysis; D016896:Treatment Outcome
D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D001378:Azasteroids; D006727:Hormone Antagonists; D000068538:Dutasteride