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

TLDR

Androgen receptor drives prostate cancer; most patients respond to androgen deprivation but inevitably relapse as hormone‑refractory, androgen‑independent disease. The study aimed to identify proteins mediating progression to androgen‑independent prostate cancer by comparing gene expression in metastatic bone marrow lesions versus primary tumors. Gene expression profiling was performed on 33 androgen‑independent bone marrow metastases and 22 laser‑capture microdissected primary prostate cancers using Affymetrix microarrays. Metastatic tumors showed upregulation of aggressive‑behavior genes, downregulation of KLF6, partial reactivation of AR signaling with 5.8‑fold AR increase, and marked elevation of androgen‑metabolizing enzymes, notably AKR1C3, confirming enhanced conversion of adrenal androgens to testosterone/DHT as a key adaptation mechanism. Cancer Res 2006; 66(5): 2815‑25.

Abstract

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. (Cancer Res 2006; 66(5): 2815-25)