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[Cancer Research 66, 2815-2825, March 1, 2006]
© 2006 American Association for Cancer Research

Endocrinology

Increased Expression of Genes Converting Adrenal Androgens to Testosterone in Androgen-Independent Prostate Cancer

Michael Stanbrough1, Glenn J. Bubley1, Kenneth Ross5, Todd R. Golub2, Mark A. Rubin4, Trevor M. Penning6, Phillip G. Febbo3 and Steven P. Balk1

1 Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School; Departments of 2 Pediatric Oncology and 3 Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; 4 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; 5 Broad Institute at Harvard and MIT, Cambridge, Massachusetts; and 6 Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Steven Balk, Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-3918; Fax: 617-667-5339; E-mail: sbalk{at}bidmc.harvard.edu.

Androgen receptor (AR) plays a central role in prostate cancer, and most patients respond to androgen deprivation therapies, but they invariably relapse with a more aggressive prostate cancer that has been termed hormone refractory or androgen independent. To identify proteins that mediate this tumor progression, gene expression in 33 androgen-independent prostate cancer bone marrow metastases versus 22 laser capture–microdissected primary prostate cancers was compared using Affymetrix oligonucleotide microarrays. Multiple genes associated with aggressive behavior were increased in the androgen-independent metastatic tumors (MMP9, CKS2, LRRC15, WNT5A, EZH2, E2F3, SDC1, SKP2, and BIRC5), whereas a candidate tumor suppressor gene (KLF6) was decreased. Consistent with castrate androgen levels, androgen-regulated genes were reduced 2- to 3-fold in the androgen-independent tumors. Nonetheless, they were still major transcripts in these tumors, indicating that there was partial reactivation of AR transcriptional activity. This was associated with increased expression of AR (5.8-fold) and multiple genes mediating androgen metabolism (HSD3B2, AKR1C3, SRD5A1, AKR1C2, AKR1C1, and UGT2B15). The increase in aldo-keto reductase family 1, member C3 (AKR1C3), the prostatic enzyme that reduces adrenal androstenedione to testosterone, was confirmed by real-time reverse transcription-PCR and immunohistochemistry. These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets. (Cancer Res 2006; 66(5): 2815-25)




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