Aberrant Wnt/β-Catenin Signaling in Pancreatic Adenocarcinoma

• Published in: Neoplasia (New York, N.Y.) Vol. 8; no. 4; pp. 279 - 289
• Main Authors: Zeng, Gang, Germinaro, Matt, Micsenyi, Amanda, Monga, Navjot K., Bell, Aaron, Sood, Ajit, Malhotra, Vanita, Sood, Neena, Midda, Vandana, Monga, Dulabh K., Kokkinakis, Demetrius M., Monga, Satdarshan P.S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2006; Elsevier
• Subjects: Adenocarcinoma - metabolism; Adult; Aged; Aged, 80 and over; beta Catenin - metabolism; cancer; DNA Mutational Analysis - methods; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; mutation; Pancreas; Pancreatic Neoplasms - metabolism; patient; tumors; Wnt Proteins - metabolism; mutation; tumors; cancer; Pancreas; patient
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.05607

Wnt/β-catenin signaling plays an important role in normal development. However, its aberrant activation is associated with several cancers. The aim of this study is to examine the Wnt/β-catenin pathway in patients with advanced pancreatic adenocarcinoma (n = 31). Paraffin sections from tumors (n = 16) and normal pancreata (n = 3) were used to determine the localization of β-catenin. An additional 15 frozen tumors, adjacent normal pancreata (n = 5), or normal pancreata (n = 4) were utilized for protein isolation. Tumors were also examined for mutations in exon 3 of the CTNNB1 gene. More than 65% of the tumors showed an increase in total β-catenin, consistent with its enhanced membranous, cytoplasmic, and nuclear localization, but only two showed mutations in CTNNB1. The majority of the remaining tumors demonstrated concurrent increases in Wnt-1 and frizzled-2 (positive regulators) and a decrease in Ser45/Thr41-phospho-β-catenin. Electrophoretic mobility shift assay demonstrated β-cateninT-cell factor binding in tumors only. Adenomatous polyposis coli and axin, which are both negative regulators, remained unchanged. Unexpectedly, total glycogen synthase kinase-3β protein was elevated in these tumors. Elevated levels of E-cadherin were also observed, although E-cadherin-β-catenin association in tumors remained unaffected. Thus, Wnt/β-catenin activation was observed in 65% of pancreatic adenocarcinomas, independently of β-catenin gene mutations in most tumors.