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Clin Cancer Res. 2019 Jul 15;25(14):4351-4362. doi: 10.1158/1078-0432.CCR-18-4024. Epub 2019 Apr 29.

EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy.

Author information

1
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. julian.puppe@uk-koeln.de.
2
Department of Obstetrics and Gynecology, Medical Faculty, University Hospital Cologne, Cologne, Germany.
3
Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
4
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Oncode Institute, Utrecht, the Netherlands.
7
Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
9
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
10
Department of Pathology, University Hospital of Cologne, Cologne, Germany.
11
CRUK Cambridge Institute, Cambridge, UK.
12
Clinic I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
#
Contributed equally

Abstract

PURPOSE:

BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("BRCA1-like") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors.

EXPERIMENTAL DESIGN:

EZH2 expression was analyzed in 497 breast cancers using IHC or RNA sequencing. We classified 370 tumors by copy-number profiles as BRCA1-like or non-BRCA1-like and examined its association with EZH2 expression. Additionally, we assessed BRCA1 loss through mutation or promoter methylation status and investigated the predictive value of EZH2 expression in a study population of breast cancer patients treated with adjuvant high-dose platinum-based chemotherapy compared with standard anthracycline-based chemotherapy. To explore whether EZH2 inhibition by GSK126 enhances sensitivity to platinum drugs in EZH2-overexpressing breast cancers we used a Brca1-deficient mouse model.

RESULTS:

The highest EZH2 expression was found in BRCA1-associated tumors harboring a BRCA1 mutation, BRCA1-promoter methylation or were classified as BRCA1 like. We observed a greater benefit from high-dose platinum-based chemotherapy in BRCA1-like and non-BRCA1-like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in Brca1-deficient mice in comparison with single agents.

CONCLUSIONS:

Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo.

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