Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma

Toll, Adam D.; Dasgupta, Abhijit; Potoczek, Magdalena; Yeo, Charles J.; Kleer, Celina G.; Brody, Jonathan R.; Witkiewicz, Agnieszka K.

doi:10.1016/j.humpath.2010.03.004

« Previous Next »Human Pathology
Volume 41, Issue 9 , Pages 1205-1209, September 2010

Implications of enhancer of zeste homologue 2 expression in pancreatic ductal adenocarcinoma☆

Adam D. Toll, MD
- Department of Pathology, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
Abhijit Dasgupta, PhD
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
Magdalena Potoczek, BS
- Department of Pathology, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
Charles J. Yeo, MD
- Department of Surgery, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
Celina G. Kleer, MD
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
Jonathan R. Brody, PhD
- Department of Pathology, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
- Department of Surgery, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
Agnieszka K. Witkiewicz, MD
- Department of Pathology, Thomas Jefferson University, Jefferson Pancreas, Biliary and Related Cancer Center, Philadelphia, PA 19107, USA
- Corresponding author. Department of Pathology, Thomas Jefferson University Hospital, Philadelphia, PA, USA

Received 17 November 2009; received in revised form 4 March 2010; accepted 5 March 2010. published online 23 June 2010.

Summary

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer deaths in the United States. Single-agent gemcitabine remains the standard treatment of advanced pancreatic adenocarcinoma. A recently discovered histone methyltransferase termed enhancer of zeste homologue 2 (EZH2) was found to be overexpressed in a variety of carcinomas including pancreatic adenocarcinoma. Silencing of E-cadherin was proposed as a mechanism by which enhancer of zeste homologue 2 mediates tumor aggressiveness, and enhancer of zeste homologue 2 depletion has been found to sensitize pancreatic cancer cells to gemcitabine. In this study, we correlated enhancer of zeste homologue 2 with E-cadherin expression in pancreatic adenocarcinoma and evaluated response to gemcitabine in relation to enhancer of zeste homologue 2 expression in tumor cells. Fifty-four pancreatic adenocarcinomas, 13 intraductal papillary mucinous neoplasms, and 6 chronic pancreatitis cases were stained with antibodies against enhancer of zeste homologue 2 and E-cadherin. Enhancer of zeste homologue 2 staining was scored from 1 to 4+ and classified as either low (1-2+ in <25% of tumor nuclei) or high (3-4+ in >25% of tumor nuclei). E-cadherin expression was scored on membrane positivity as follows: 0 (0%-10%), 1 (10%-25%), 2 (25%-75%), and 3 (>75%). High enhancer of zeste homologue 2 expression in pancreatic adenocarcinoma was significantly associated with decreased E-cadherin expression and more aggressive disease. There was significantly longer survival in gemcitabine-treated patients with low versus high enhancer of zeste homologue 2 expression. High enhancer of zeste homologue 2 expression was detected in intraductal papillary mucinous neoplasms with moderate to severe dysplasia, but not in chronic pancreatitis. Our study suggests that E-cadherin down-regulation may lead to enhancer of zeste homologue 2–mediated invasion and metastasis.

Keywords: EZH2, Pancreatic ductal adenocarcinoma