Dysregulation of beta-catenin expression correlates with tumor differentiation in pancreatic duct adenocarcinoma.

BACKGROUND: beta-Catenin functions as an integral part of the E-cadherin/catenin adhesion complex to maintain epithelial cell integrity. beta-Catenin also functions as part of the Wnt signal transduction pathway to transmit growth-promoting signals to the nucleus via its interactions with Tcf/Lef transcription factors. Previous reports have demonstrated altered beta-catenin expression in numerous tumor types; however, reports regarding beta-catenin expression in pancreatic cancer have been conflicting. METHODS: beta-Catenin expression was examined in 10 pancreatic cancer cell lines by Western and Northern analysis and by immunofluorescence. Expression was also examined by immunohistochemistry in 57 primary pancreatic cancers and 7 foci of carcinoma-in-situ. RESULTS: Reduced expression of beta-catenin was observed in 4 of 10 pancreatic cancer cell lines. Reduced membranous expression was noted in 32 pancreatic cancers (56%) and correlated with loss of tumor differentiation. Nuclear beta-catenin expression was identified in two tumors (4%). beta-Catenin expression was present in all seven foci of carcinoma-in-situ; however, nuclear expression was predominant in four of the seven cases. CONCLUSIONS: Alterations in beta-catenin expression are common in pancreatic cancer; however, signaling and adhesion functions may be perturbed at different times during tumor progression. Therefore, dysregulation of beta-catenin may contribute to the development and progression of this disease through distinct mechanisms.

beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer.

Studies of Wnt activation in gastric cancer have yielded conflicting results. The goals of this study were to determine the frequency of Wnt pathway activation and beta-catenin mutation in these tumors. Three hundred eleven gastric cancers were examined for beta-catenin expression by immunostaining and dissected using laser capture microscopy to obtain DNA from those tumors with nuclear beta-catenin. Exon 3 of beta-catenin was amplified using PCR and sequenced. Ninety gastric cancers (29%) displayed nuclear beta-catenin. DNAs from 73 tumors were amplified and sequenced; 19 (26%) contained mutations in exon 3 of beta-catenin, whereas no mutations were detected in 19 tumors negative for beta-catenin nuclear staining (P < 0.05). Most mutations were adjacent to or abolished known regulatory phosphorylation sites. Mutations in exon 3 of beta-catenin are common in gastric cancer that display nuclear beta-catenin. These results suggest that Wnt pathway activation contributes to carcinogenesis in a subset of gastric adenocarcinomas.