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

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.

• Authors: Michael Stanbrough, Glenn J Bubley, Kenneth Ross, Todd R Golub, Mark A Rubin, Trevor M Penning, Phillip G Febbo, Steven P Balk
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 5 Pg. 2815-25 (Mar 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16510604 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgens
• Receptors, Androgen
• Testosterone
• 3-Hydroxysteroid Dehydrogenases
• Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C2 protein, human
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3

Topics

• 3-Hydroxysteroid Dehydrogenases (biosynthesis, genetics)
• Aldo-Keto Reductase Family 1 Member C3
• Androgens (metabolism)
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Hydroxyprostaglandin Dehydrogenases (biosynthesis, genetics)
• Hydroxysteroid Dehydrogenases (biosynthesis, genetics)
• Male
• Neoplasms, Hormone-Dependent (genetics, metabolism)
• Prostatic Neoplasms (genetics, metabolism)
• Receptors, Androgen (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Testosterone (biosynthesis)