Research article

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

Julian Puppe^1,2 , Rinske Drost³ , Xiaoling Liu^3,8 , Simon A Joosse⁴ , Bastiaan Evers³ , Paulien Cornelissen-Steijger¹ , Petra Nederlof⁵ , Qiang Yu⁶ , Jos Jonkers^3* , Maarten van Lohuizen^1* and Alexandra M Pietersen^1,7*

¹  Molecular Genetics and Cancer Genomics Centre, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

²  Institute of Physiological Chemistry, The Medical Faculty Carl-Gustav Carus, Fetscherstraß 74, 01307 Dresden, Germany

³  Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

⁴  Department of Experimental Therapy, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

⁵  Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

⁶  Molecular Pharmacology, Genome Institute of Singapore, 60 Biopolis Street, 138672 Singapore

⁷  National Cancer Centre Singapore/Duke-NUS GMS, 11 Hospital Drive, 169610 Singapore

⁸  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.