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Clinical Cancer Research Vol. 11, 4365-4371, June 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Steroid 5{alpha}-Reductase Isozymes I and II in Recurrent Prostate Cancer

Mark A. Titus4, Christopher W. Gregory1,4, O. Harris Ford, III4, Michael J. Schell3,4, Susan J. Maygarden1 and James L. Mohler1,2,4,5,6

Authors' Affiliations: Departments of 1 Pathology and Laboratory Medicine, 2 Surgery, 3 Biostatistics, and 4 UNC Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, 5 Department of Urologic Oncology, Roswell Park Cancer Institute, and 6 Department of Urology, University at Buffalo School of Medicine and Biotechnology, Buffalo, New York

Requests for reprints: Mark A. Titus, UNC Lineberger Comprehensive Cancer Center, CB#7295, University of North Carolina, Chapel Hill, NC 27599-7295. Phone: 919-966-9257; Fax: 919-966-3015; E-mail: matitus{at}med.unc.edu.

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 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 androgen-stimulated prostate cancer specimens. Isozyme expression was examined in microarray sections and immunoblots using S5{alpha}RI and S5{alpha}RII 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 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 S5{alpha}RII, 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 dihydrotestosterone biosynthesis and may prevent or delay growth of recurrent prostate cancer.

Key Words: recurrent prostate cancer • dihydrotestosterone • steroid 5{alpha}-reductase isozyme I and II • immunohistochemistry • metabolomics




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