Expression of ERRP in Normal and Neoplastic Pancreata and Its Relationship to Clinicopathologic Parameters in Pancreatic Adenocarcinoma

Abstract

Epidermal growth factor (EGF) and its receptor (EGFR) play crucial roles in cellular signaling in many malignancies, including pancreatic neoplasia. Attenuation of EGFR signaling has been considered novel strategy for the management of human malignancies in several ongoing clinical trials. We recently isolated a novel negative regulator of EGFR, termed EGF receptor related protein (ERRP), whose expression appears to attenuate EGFR activation. In the current study, the expression of ERRP in normal and neoplastic pancreas was investigated and correlated with the clinicopathologic parameters in pancreatic ductal adenocarcinoma (DA). Using rabbit polyclonal antibody that specifically interacts with ERRP, immunohistochemical staining was performed on 45 benign pancreata and 106 cases of DA. The intensity and percentage of cells with cytoplasmic and membranous staining were scored as 0, 1, 2, or 3. A combined score was calculated as intensity x percent/3, and for comparative analysis, the data were arbitrarily divided into three groups: <20, 20-49, and > or =50. The expression of ERRP was correlated with patient age, gender, race, tumor size, stage, grade, and survival. ERRP was expressed in most benign ductal epithelium and islet cells, but not in normal acinar cells. In pancreatic ductal adenocarcinoma, ERRP expression frequency decreased progressively from well (WD) to moderate (MD) to poorly differentiated (PD) carcinoma (58%, 43%, and 15% respectively, < 0.001). ERRP expression was correlated with survival in DA showing decreased median survival with decreased ERRP score ( = 0.0035). Median survival of the lower intensity (0 or 1) group was less than that of the higher intensity (2 or 3) group (8 14 months, = 0.002). The higher expressing group (> or =50% of cells) had longer median survival (17 months) than the lower expressing (<50% of cells) group (10 months, = 0.003). Stepwise multiple regression analyses revealed that ERRP expression score and tumor grade are the significant predictors of survival in pancreatic ductal carcinomas ( < 0.03). ERRP is usually expressed in benign ductal epithelium, but not in ductal adenocarcinoma. Its expression decreases with decreasing tumor differentiation. Low levels of ERRP are associated with poor clinical outcome, suggesting that progressive loss of ERRP, a negative regulator of EGFR, may partly stimulate aggressive tumor cell growth in pancreatic adenocarcinoma.