Repression of E-Cadherin by the Polycomb Group Protein EZH2 in Pancreatic Cancer
AD Toll, A Dasgupta, M Potoczek, CG Kleer, JR Brody, AK Witkiewicz. Thomas Jefferson University Hospital, Philadelphia, PA; University of Michigan, Ann Arbor, MI
Background: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer deaths in the United States. Single-agent gemcitabine remains the standard treatment for advanced PDA, which has shown improvement in disease-related symptoms and a modest benefit in survival. A recently discovered histone methyltransferase termed enhancer of zeste homologue 2 (EZH2) was found to be overexpressed in a variety of carcinomas including PDA. Silencing of E-cadherin was proposed as a mechanism by which EZH2 mediates tumor aggressiveness. Furthermore, in-vitro studies showed EZH2 depletion sensitizes pancreatic cancer cells to gemcitabine. In this study we correlated EZH2 with E-cadherin expression in PDA, and evaluated response to gemcitabine in relation to EZH2 expression.
Design: 43 PDAs, 14 intraductal papillary mucinous neoplasms (IPMNs), and 5 chronic pancreatitis (CP) cases were stained with EZH2 (BD Bioscience; 1:25) and E-cadherin (Zymed; 1:1,000). Cases with diffuse weak staining, or strong staining in less than 30% of tumor nuclei were considered to have low EZH2 expression. High EZH2 expression was defined as strong nuclear staining in >30% of tumor cells. E-cadherin expression was scored on membrane positivity as follows: 0 (0-10%); 1 (10_25%); 2 (25-75%), and 3 (>75%). E-cadherin scores were considered normal at 3, reduced at 2, and negative at 1 or 0. Statistical analysis was performed using Fisher's exact and Kruskal-Wallis tests, depending on the discrete or continuous nature of the other factors. A Kaplan-Meier curve was stratified by EZH2 expression to assess survival.
Results: High EZH2 expression in PDA was significantly associated with decreased E-cadherin expression (70% vs. 35%), node-positivity (82% vs. 40%), and larger tumor size (4 cm vs. 2.4 cm). There was a trend for longer survival (35 vs. 15 months) in gemcitabine treated patients with low vs. high EZH2 expression. High EZH2 expression was detected in IMPN with moderate-severe dysplasia, however not in CP.
Conclusions: Our study suggests that E-cadherin downregulation may lead to EZH2-mediated invasion and metastasis. While strong diffuse EZH2 expression is seen in PDA, overexpression may be present in IPMN.
Category: Liver & Pancreas
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 208, Tuesday Afternoon