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BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A

Julian Puppe1,2 email, Rinske Drost3 email, Xiaoling Liu3,8 email, Simon A Joosse4 email, Bastiaan Evers3 email, Paulien Cornelissen-Steijger1 email, Petra Nederlof5 email, Qiang Yu6 email, Jos Jonkers3* email, Maarten van Lohuizen1* email and Alexandra M Pietersen1,7* email

Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Institute of Physiological Chemistry, The Medical Faculty Carl-Gustav Carus, Fetscherstraß 74, 01307 Dresden, Germany

Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Department of Experimental Therapy, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

Molecular Pharmacology, Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore

National Cancer Centre Singapore/Duke-NUS GMS, 11 Hospital Drive, 169610 Singapore

Current address: Biomedical Analysis Center, Tsinghua University, Beijing 100084, PR China

author email corresponding author email* Contributed equally

Breast Cancer Research 2009, 11:R63doi:10.1186/bcr2354

Published: 26 August 2009


See related editorial by Wicha, http://breast-cancer-research.com/content/11/5/108

Abstract

Introduction

Treatment of breast cancer is becoming more individualized with the recognition of tumor subgroups that respond differently to available therapies. Breast cancer 1 gene (BRCA1)-deficient tumors are usually of the basal subtype and associated with poor survival rates, highlighting the need for more effective therapy.

Methods

We investigated a mouse model that closely mimics breast cancer arising in BRCA1-mutation carriers to better understand the molecular mechanism of tumor progression and tested whether targeting of the Polycomb-group protein EZH2 would be a putative therapy for BRCA1-deficient tumors.

Results

Gene expression analysis demonstrated that EZH2 is overexpressed in BRCA1-deficient mouse mammary tumors. By immunohistochemistry we show that an increase in EZH2 protein levels is also evident in tumors from BRCA1-mutation carriers. EZH2 is responsible for repression of genes driving differentiation and could thus be involved in the undifferentiated phenotype of these tumors. Importantly, we show that BRCA1-deficient cancer cells are selectively dependent on their elevated EZH2 levels. In addition, a chemical inhibitor of EZH2, 3-deazaneplanocin A (DZNep), is about 20-fold more effective in killing BRCA1-deficient cells compared to BRCA1-proficient mammary tumor cells.

Conclusions

We demonstrate by specific knock-down experiments that EZH2 overexpression is functionally relevant in BRCA1-deficient breast cancer cells. The effectiveness of a small molecule inhibitor indicates that EZH2 is a druggable target. The overexpression of EZH2 in all basal-like breast cancers warrants further investigation of the potential for targeting the genetic make-up of this particular breast cancer type.


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