Steroid 5α-reductase isozymes I and II in recurrent prostate cancer

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 5α-reducing capability. The aim of this study was to characterize steroid 5α-reductase isozymes I (S5αRI) and II (S5αRII) 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 androgen-stimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5αRI and S5αRII polyclonal antibodies. Isozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgen-stimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5αRI expression than S5αRII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P < 0.0001); mean expression was 125, 150, and 1.15 for S5αRI versus 10, 29, and 37 for S5αRII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P > 0.05). Immunoblots confirmed immunohistochemistry; S5αRI was expressed in recurrent prostate cancer specimens and S5αRII was not detected. The activity of S5αRI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5αRII (30.7 pmol/mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5αRII toward S5αRI in recurrent prostate cancer. Dual inhibition of S5αRI and S5αRII should reduce dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.