Significantly higher expression levels of androgen receptor are associated with erythroblastosis virus E26 oncogene related gene positive prostate cancer

Abstract

Erythroblastosis virus E26 related gene (ERG) overexpression is correlated with the TMPRSS2-ERG fusion gene, a rearrangement known to be present in about 50% of cases of prostate cancer. Androgen receptor (AR) is a known regulator of the TMPRSS2 gene. Despite knowledge of this relationship, limited data is available on the specific relationship of AR expression to TMPRSS2-ERG fusion (ERG) status in prostate cancer (PCa). We used multiplexed immunohistochemistry, multispectral imaging technology and tissue microarray (TMA) to elucidate this relationship. Two prostate tissue microarrays were created from two cohorts of hormonal naïve patients' prostatectomy specimens: progression TMA (pTMA, from 95 PCa patients) and outcome TMA (oTMA, from 183 PCa patients with at least 5-year follow-up information). Each of the two TMAs were triple-stained with ERG, AR and E-cadherin antibodies and visualized with a different chromogen. We found marked difference in AR expression levels between ERG positive (ERG(+)) and ERG negative (ERG(-)) prostate cancer. The difference was significant in localized (pT2) prostate cancer. We also found that AR expression levels were significantly higher in PCa tissue compared to benign prostate tissue, with the highest expression levels in ERG(+) metastatic cancer. Neither AR nor ERG expression was associated with clinical outcome. Our findings confirm that TMPRSS2-ERG fusion is AR-dependent and is associated with increased AR expression. Our data suggest that the AR pathway may play an important role in the development of ERG(+) PCa and ERG status may be useful in stratifying PCa patients for hormonal therapy.

Keywords: AR; ERG; TMPRSS2; prostate cancer.

Figure 1

Multiplexed Immunohistochemistry and multispectral imaging. The spectral library of 4 chromogens (DAB, Warp Red, Vina Green and hematoxylin) was built using Nuance software (A). An image of PCa stained with three antibodies (E-Cad, AR and ERG) (B). Images of unmixed signals (DAB, Warp Red, Vina Green and hematoxylin) of PCa with the spectral library (C-F).

Figure 2

Nuclear AR and ERG expression levels of the prostate tissue samples from the two PCa cohorts. Expression levels of both nuclear AR and ERG are significantly higher in PCa and HGPIN compared to benign prostatic tissue. AR expression levels are significantly increased in PCa tissue compared to benign prostatic tissue (p < 0.01). The highest level of AR expression is observed in PCa metastases (mean OD = 0.29) (A). However, neither AR nor ERG expression seems to correlate with patients’ outcome (B).

Figure 3

Nuclear AR expression levels of the prostate tissue samples from the two PCa cohorts. AR expression levels in ERG⁺ PCa overall are much higher than those in ERG^- PCa and the difference is statistically significant only in localized PCa group in cohort 1 (A) and in no-recurrence PCa group in cohort 2 (B) (p < 0.01).