Purpose. 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.Experimental Design. 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 androgenregulated 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.

Purpose: Prostate cancer recurs during androgen deprivation therapy despite reduced circulating androgens. We showed that recurrent prostate cancer tissue has testosterone levels similar to androgen-stimulated benign prostate, whereas dihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation. The altered testosterone/dihydrotestosterone ratio in recurrent prostate cancer suggests loss of 5a-reducing capability. The aim of this study was to characterize steroid 5a-reductase isozymes I (S5aRI) and II (S5aRII) in prostate tissues. Experimental Design: A tissue microarray was constructed from 22 recurrent prostate cancer specimens and matched pairs of androgen-stimulated benign prostate and androgen-stimulated prostate cancer from 23 radical prostatectomy specimens. Immunoblots were constructed from eight recurrent prostate cancers, eight androgen-stimulated benign prostate, and eight androgenstimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5aRI and S5aRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgenstimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5aRI expression than S5aRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P < 0.0001); mean expression was 125, 150, and 115 for S5aRI versus 10, 29, and 37 for S5aRII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P > 0.05). Immunoblots confirmed immunohistochemistry; S5aRI was expressed in recurrent prostate cancer specimens and S5aRII was not detected. The activity of S5aRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5aRII (30.7 pmol/ mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5aRII toward S5aRI in recurrent prostate cancer. Dual inhibition of S5aRI and S5aRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.Androgen target cells in peripheral tissues use testosterone to activate androgen receptor, which interacts with androgen response elements in DNA to regulate gene transcription. Alternatively, intracellular testosterone acts as a prohormone that is converted to dihydrotestosterone, a more potent androgen receptor ligand. In the prostate, an intracrine pathway (1) uses the enzyme steroid 5a-reductase (EC 1.3.99.5) to metabolize testosterone to dihydrotestosterone. The adrenal androgen androstenedione is also converted to 5a-reduced androstanedione by steroid 5a-reductase in the prostate (2) and androstenedione has been implicated as a source of dihydrotestosterone in prostate tissue after castration (3).Steroid 5a-reductase is a membrane-associated, NADPHdependent enzyme that catalyzes the irreversible stereospec...

CARM1 is essential for AR function and may play a role in prostate cancer progression. CARM1 may represent a novel therapeutic target in prostate cancer.

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AR protein expression was 22% higher in the benign prostate and 81% higher in the CaP of black African compared with white men. CaP may occur at a younger age and progress more rapidly in black than in white men due to racial differences in androgenic stimulation of the prostate.