Research article
BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A
-
* Corresponding authors: Jos Jonkers j.jonkers@nki.nl - Maarten van Lohuizen m.v.lohuizen@nki.nl - Alexandra M Pietersen gmsamp@nus.edu.sg
- † Equal contributors
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
Breast Cancer Research 2009, 11:R63 doi:10.1186/bcr2354
See related editorial by Wicha, http://breast-cancer-research.com/content/11/5/108
Published: 26 August 2009Abstract
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.