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 clihydrotestosterone levels were reduced 82% to 1.45 nmol/L, sufficient for androgen receptor activation. The altered testosterone/clihydrotestosterone ratio in recurrent prostate cancer suggests loss of 5 alpha-reducing capability. The aim of this study was to characterize steroid 5 alpha-reductase isozymes I (S5 alpha RI) and II (S5 alpha RII) 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 S5 alpha R1 and S5 alpha RII polyclonal antibodies. lsozyme activities were measured in 12 recurrent prostate cancer, 12 androgen-stimulated benign prostate, and 12 androgenstimulated prostate cancer specimens. Results: Nuclear immunostaining exhibited higher S5 alpha RI expression than S5 alpha RII in recurrent prostate cancer, androgen-stimulated benign prostate, and androgen-stimulated prostate cancers (P < 0.0001); mean expression was 125, 150, and 115 for S5 alpha RI versus 10, 29, and 37 for S5URII, respectively. Cytoplasmic immunostaining was moderate and similar for both isozymes in the three tissue types (P > 0.05). Immunoblots confirmed immunohistochemistry; S5 alpha RI was expressed in recurrent prostate cancer specimens and S5 alpha RII was not detected. The activity of S5 alpha RI (114.4 pmol/mg epithelial protein/minute) was 3.7-fold higher than S5 alpha RII (30.7 pmol/ mg epithelial protein/minute) in recurrent prostate cancer specimens. Conclusions: Expression levels and isozyme activity shifts from S5 alpha RII toward S5 alpha RI in recurrent prostate cancer. Dual inhibition of S5 alpha RI and S5 alpha RII should reduce clihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.