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Cancer research DOI:10.1158/0008-5472.CAN-05-4000

Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer.

Publication TypeJournal Article
Year of Publication2006
AuthorsStanbrough, M, Bubley, GJ, Ross, K, Golub, TR, Rubin, MA, Penning, TM, Febbo, PG, Balk, SP
JournalCancer research
Volume66
Issue5
Pages2815-25
Date Published2006/03/01
ISSN0008-5472
Abstract

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.

URLhttp://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=16510604
DOI10.1158/0008-5472.CAN-05-4000
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/16510604?dopt=Abstract