Purpose: BRCA1-deficient breast cancers carry a specific overexpressing breast cancers we used a Brca1-deficient mouse DNA copy-number signature ("BRCA1-like") and are hyper-model. sensitive to DNA double-strand break (DSB) inducing com-Results: The highest EZH2 expression was found in BRCA1-pounds. Here, we explored whether (i) EZH2 is overexpressed associated tumors harboring a BRCA1 mutation, BRCA1-pro-in human BRCA1-deficient breast tumors and might predict moter methylation or were classified as BRCA1 like. We sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition observed a greater benefit from high-dose platinum-based potentiates cisplatin efficacy in Brca1-deficient murine mam-chemotherapy in BRCA1-like and non-BRCA1–like patients mary tumors. with high EZH2 expression. Combined treatment with the Experimental Design: EZH2 expression was analyzed in EZH2 inhibitor GSK126 and cisplatin decreased cell prolifer-497 breast cancers using IHC or RNA sequencing. We classified ation and improved survival in Brca1-deficient mice in com-370 tumors by copy-number profiles as BRCA1-like or non-parison with single agents. BRCA1–like and examined its association with EZH2 expres-Conclusions: Our findings demonstrate that EZH2 is sion. Additionally, we assessed BRCA1 loss through mutation expressed at significantly higher levels in BRCA1-deficient or promoter methylation status and investigated the predictive breast cancers. EZH2 overexpression can identify patients value of EZH2 expression in a study population of breast with breast cancer who benefit significantly from intensified cancer patients treated with adjuvant high-dose platinum-DSB-inducing platinum-based chemotherapy independent based chemotherapy compared with standard anthracycline-of BRCA1-like status. EZH2 inhibition improves the anti-based chemotherapy. To explore whether EZH2 inhibition tumor effect of platinum drugs in Brca1-deficient breast by GSK126 enhances sensitivity to platinum drugs in EZH2-tumors in vivo.