Elsevier

Human Pathology

Volume 41, Issue 9, September 2010, Pages 1205-1209
Human Pathology

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

https://doi.org/10.1016/j.humpath.2010.03.004Get rights and content

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.

Introduction

Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States with more than 35,000 annual deaths [1]. Surgical resection is the only potentially curative treatment. However, only a minority of patients meet the criteria for surgery; and thus, more than 80% of patients have metastatic or unresectable disease at the time of diagnosis. Single-agent gemcitabine remains the standard treatment of advanced PDA, which has shown improvement in disease-related symptoms and a modest benefit in survival [2]. More recently, gemcitabine has been used in combination with targeted therapies. Based on results from recent clinical trials, gemcitabine in combination with epidermal growth factor receptor inhibitor is considered the standard of care for advanced PDA patients in North America [2].

Epigenetic silencing of tumor suppressor genes has become a recognized part of tumorigenesis and is a recognized hallmark of pancreatic cancer [3], [4]. Gene expression regulation through epigenetic silencing occurs through either DNA methylation or posttranslational modification of histone proteins [5]. One family of polycomb group proteins is capable of methylating both DNA and core histones. These proteins temporally and spatially restrict tissue stem cells while maintaining proliferative potential and establishing terminal differentiation patterns [6]. Polycomb group complexes contain a histone methyltransferase enhancer, zeste homologue 2 (EZH2), which has previously been shown to be overexpressed in a variety of carcinomas including PDA [5]. Furthermore, EZH2 depletion in pancreatic cancer cell lines rendered cells sensitive to gemcitabine by inducing apoptosis [5]. Additional work demonstrated that EZH2 mediates transcriptional silencing of the tumor suppressor gene E-cadherin, and inhibitors of EZH2 can attenuate malignant transformation in breast and prostate cancer cell lines [7].

In this study, we examined EZH2 and E-cadherin expression in PDA and correlated the expression of these candidate biomarkers with patient survival and response to gemcitabine treatment. In addition, we evaluated EZH2 expression in tissues from precursor lesions to PDA, intraductal papillary mucinous neoplasms (IPMNs), as well as chronic pancreatitis.

Section snippets

Methods

Fifty-four surgically resected PDAs, 13 IPMNs (5 cases with mild dysplasia, 5 with moderate dysplasia, and 3 with severe dysplasia), and 6 chronic pancreatitis cases were obtained from the Department of Surgical Pathology of Thomas Jefferson University Hospital. Eight IPMNs were intestinal type, 1 was gastric, and 4 were pancreaticobiliary types. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded 4-μm sections. Representative sections were stained with both EZH2 (BD

Association between EZH2 and E-cadherin expression in PDA

High EZH2 expression in PDA was associated with decreased E-cadherin expression in 70% of cases (compared with 35% for low EZH2 expression), node positivity (86% versus 48%), and larger tumor size (median of 4 versus 2.5 cm) (Table 1, Fig. 1). All well-differentiated PDAs showed normal expression of E-cadherin. Moderate and poorly differentiated PDAs showed normal E-cadherin expression in 44% and 36% of cases, respectively. Other poor prognostic parameters including extrapancreatic extension

Discussion

The results of our study demonstrate that EZH2 overexpression in PDA is associated with low E-cadherin expression, increased node positivity, and larger tumor size. The EZH2 expression was related to the degree of dysplasia in IPMN. High EZH2 expression was seen only in IPMN cases with at least moderate dysplasia. Chronic pancreatitis was essentially negative or showed low EZH2 expression. Together, these findings suggest that increased EZH2 expression levels may be an early, important event in

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