Abstract
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. 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. 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. 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.
Highlights
The histone methyltransferase EZH2 is a member of the polycomb repressive complex 2 (PRC2) and catalyzes the trimethylation of lysine 27 on histone 3 (H3K27me3; ref. 1)
The highest EZH2 expression was found in BRCA1associated 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
Summary
The histone methyltransferase EZH2 (enhancer of zeste homolog 2) is a member of the polycomb repressive complex 2 (PRC2) and catalyzes the trimethylation of lysine 27 on histone 3 (H3K27me; ref. 1). EZH2 is implicated in cancer cell proliferation, invasion, as well as metastasis, and it is associated with a poor outcome in breast cancer [6,7,8,9,10]. BRCA1-mutant breast cancers are characterized by a triplenegative (hormone receptor–negative and HER2-negative) phenotype (TNBC), a basal-like molecular subtype and associated.
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