Epithelial-Cadherin and β-Catenin Expression Changes in Pancreatic Intraepithelial Neoplasia

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Abstract
Purpose: Cadherins and associated catenins are important mediators of epithelial cell-cell adhesion, as well as the Wnt-signaling pathway. Significant changes in their expression or structure have been implicated in malignancy. This study aimed to investigate the epithelial-cadherin (E-cadherin) and β-catenin expression changes during multistage, pancreatic ductal carcinogenesis. Experimental Design: Ninety-four Whipple resection specimens were retrieved from the surgical pathology files of the University Health Network (Toronto, Canada), from which tissue microarray blocks containing 36 pancreatic ductal adenocarcinomas, 34 PanIN-1A lesions, 28 PanIN-1B lesions, 27 PanIN-2 lesions, 16 PanIN-3 lesions, and 32 normal ducts were constructed. The E-cadherin, β-catenin, and the phosphorylated glycogen synthase kinase-3β of the Wnt/β-catenin pathway were immunohistochemically evaluated in these duct/PanIN lesions. Results: There was marked increase in the cytoplasmic E-cadherin expression in PanIN lesions (P < 0.0001) and adenocarcinoma (P = 0.005) compared with normal pancreatic ducts. In contrast, reduced/loss of E-cadherin membranous expression was also significant in ductal adenocarcinoma compared with both the PanIN lesions (P < 0.0001) and normal ducts (P = 0.05). The β-catenin expression showed significantly more frequent aberrant nuclear localization in high-grade PanIN lesions, particularly PanIN2 and in adenocarcinoma compared with normal ducts or low grade PanIN lesions (P < 0.0001). However, there was a lack of correlation between phosphoSer9-glycogen synthase kinase-3β cytoplasmic expression and β-catenin aberrant nuclear expression (P = 0.07). Conclusions: Aberration in the expression of E-cadherin and its associated β-catenin is evident in pre-invasive (PanIN) neoplastic pancreatic duct cells, suggesting involvement of pathways leading to β-catenin stabilization during pancreatic duct cell carcinogenesis.