ERG Expression Levels in Prostate Tumors Reflect Functional Status of the Androgen Receptor (AR) as a Consequence of Fusion of ERG with AR Regulated Gene Promoters

摘要

Expression of the ERG proto-oncogene, is activated in 50-70% of prostate tumors by androgen receptor (AR) mediated signals due to the fusion of AR regulated promoters (primarily TMPRSS2 and to a lesser extent SLC45A3 and NDRG1) to the ERG protein coding sequence. Our previous studies of quantitative expression levels of ERG or TMPRSS2-ERG fusion transcripts have noted that relatively low or no ERG expression in prostate tumors significantly associated with progressive disease. Here, we have tested the hypothesis that ERG expression levels in prostate tumor cells reflect AR transcriptional regulatory function in a given biological context of the tumor progression. Therefore tumors with lower ERG may represent a subset with attenuated AR signaling. Expression of ERG and other AR regulated genes were evaluated in a GeneChip dataset obtained from a panel of laser capture micro-dissected well/moderately differentiated (WD) or poorly differentiated (PD) tumor cells derived from primary tumors of patients, who had no prior androgen ablation treatment. Overall, ERG expression pattern was similar to that of other AR regulated genes. Strikingly low frequency of ERG expression was noted in PD tumor cells (30%) in comparison to WD tumor cells (80%), suggesting for subdued AR function in a significant fraction of tumors with genomic alterations of ERG. By integrating ERG into a panel of defined AR target genes, we developed a cumulative AR Function Index (ARFI), which if validated may have future potential in stratifying patients for targeted therapy on the basis of overall AR functional status in primary tumors.