The androgen axis in recurrent prostate cancer.
OBJECTIVE
Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen-independent. High levels of expression of androgen receptor and androgen receptor-regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence.


METHODS
Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied. Androgen receptor expression was measured using monoclonal antibody and automated digital video image analysis. Tissue androgens were measured using radioimmunoassay.


RESULTS
Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer (mean optical density, 0.284 +/- SD 0.115 and percentage positive nuclei, 83.7 +/- 11.6) was similar to benign prostate (mean optical density, 0.315 +/- 0.044 and percentage positive nuclei, 77.3 +/- 13.0). Tissue levels of testosterone were similar in recurrent prostate cancer (2.78 +/- 2.34 pmol/g tissue) and benign prostate (3.26 +/- 2.66 pmol/g tissue). Tissue levels of dihydrotestosterone, dehydroepiandrosterone, and androstenedione were lower (Wilcoxon, P = 0.0000068, 0.00093, and 0.0089, respectively) in recurrent prostate cancer than in benign prostate, and mean dihydrotestosterone levels, although reduced, remained 1.45 nM. Androgen receptor activation in recurrent prostate cancer was suggested by the androgen-regulated gene product, prostate-specific antigen, at 8.80 +/- 10.80 nmol/g tissue.


CONCLUSIONS
Testosterone and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor. Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue.
Mohler
James L
JL
Department of Surgery, Division of Urology, Pathology and Laboratory Medicine, University of North Carolina-Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA. james.mohler@roswellpark.org
Gregory
Christopher W
CW
Ford
O Harris
OH
Kim
Desok
D
Weaver
Catharina M
CM
Petrusz
Peter
P
Wilson
Elizabeth M
EM
French
Frank S
FS
D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism*; D000735:Androstenedione / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D018715:Microscopy, Video; D008875:Middle Aged; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000473:pathology; D011863:Radioimmunoassay; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000378:metabolism; D012008:Recurrence
D000728:Androgens; D000911:Antibodies, Monoclonal; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D017430:Prostate-Specific Antigen