Introduction: Gene fusion of the TMPRSS2 promoter and ERG that gives rise to aberrant ERG expression is detected in over 50% of prostate cancers (CaP). ERG overexpression abrogates cell differentiation, promotes cell invasion and epithelial to mesenchymal transition, and additional Pten loss or AKT up-regulation enhances the transformation into well-differentiated prostate adenocarcinoma. Annexin A2 (ANXA2) is a calcium–dependent phospholipid–binding protein that regulates cell adhesion, cellular junction formation, actin remodeling and genesis of cell polarity. Evidence from a variety of malignancies suggests that ANXA2 is vital for promoting adhesion, migration and metastasis in cancer cells. In CaP, ANXA2 expression is lost or reduced, however, is increased in high grade tumors. Microarray gene expression studies have shown an inverse correlated ERG and ANXA2 expression. We examined the cancer associated functions of ERG and ANXA2 such as cell invasion, cell migration and cell polarity in CaP cell lines.
Methods: ANXA2 and ERG cellular localization were monitored using fluorescence microscopy. The prostate specific transcriptional initiation site of ANXA2 was defined by 5’–RACE. Ch-IP Assay was used to show the recruitment of ERG to the ANXA2 promoter. Cases consisting of well differentiated and poorly differentiated CaP with and without TMPRSS2-ERG fusion were stained with ANXA2 and ERG antibodies to determine correlation in expression.
Results: The inverse correlation between ERG and ANXA2 protein expression was confirmed by ERG knockdown experiments in VCaP cells. ERG overexpression in prostate adenocarcinoma is correlated with the loss ANXA2 expression in 90% of cases examined. A subset of ERG positive tumors exhibit small clusters of cells with clonal expression of ANXA2. We evaluated the patterns of ERG-ANXA2 expression against available clinical-pathological features.
Conclusions: Our findings suggest that the expression of ANXA2 and its function in establishing cell polarity and cellular junctions may be disrupted by ERG overexpression through the transcriptional repression of ANXA2. We hypothesize that the reemergence of ANXA2 expression in advanced tumors reflects the accumulation of genetic hits that resulted in a more aggressive tumor with higher metastatic capacity. An IHC based assay with combined ERG and ANXA2 antibody cocktail could enhance the pathological evaluation of prostate tumors discern the re-expression of ANXA2 in ERG positive tumors and improve the prognosis and treatment of CaPs.
This research was in part supported by the National Cancer Institute R01CA162383 grant to S. S. and USU–CPDR funds.
Citation Format: Nick E. Griner, Shyh-Han Tan, Denise Young, Albert Dobi, Gyorgy Petrovics, Isabell Sesterhenn, Shiv Srivastava. The expression of ERG oncoprotein and Annexin A2 show a strong inverse correlation in prostate cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5117. doi:10.1158/1538-7445.AM2013-5117