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Cancer Res 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 Res
Date Published2006 Mar 01
Keywords3-Hydroxysteroid Dehydrogenases, Androgens, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Humans, Hydroxyprostaglandin Dehydrogenases, Hydroxysteroid Dehydrogenases, Male, Neoplasms, Hormone-Dependent, Prostatic Neoplasms, Receptors, Androgen, Reverse Transcriptase Polymerase Chain Reaction, Testosterone

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.


Alternate JournalCancer Res.
PubMed ID16510604
Grant ListR01 CA90744-02 / CA / NCI NIH HHS / United States