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

Abstract

BRCA1-deficient breast cancers carry a specific DNA copy-number signature ("<i>BRCA1-like</i>") and are hypersensitive to DNA double-strand break (DSB) inducing compounds. Here, we explored whether (i) EZH2 is overexpressed in human <i>BRCA1</i>-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in <i>Brca1</i>-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 <i>BRCA1</i>-like or non-<i>BRCA1</i>-like and examined its association with EZH2 expression. Additionally, we assessed <i>BRCA1</i> 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 <i>Brca1</i>-deficient mouse model. The highest EZH2 expression was found in BRCA1-associated tumors harboring a <i>BRCA1</i> mutation, <i>BRCA1</i>-promoter methylation or were classified as <i>BRCA1</i> like. We observed a greater benefit from high-dose platinum-based chemotherapy in <i>BRCA1</i>-like and non-<i>BRCA1</i>-like patients with high EZH2 expression. Combined treatment with the EZH2 inhibitor GSK126 and cisplatin decreased cell proliferation and improved survival in <i>Brca1</i>-deficient mice in comparison with single agents. Our findings demonstrate that EZH2 is expressed at significantly higher levels in <i>BRCA1</i>-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who benefit significantly from intensified DSB-inducing platinum-based chemotherapy independent of <i>BRCA1</i>-like status. EZH2 inhibition improves the antitumor effect of platinum drugs in <i>Brca1</i>-deficient breast tumors <i>in vivo</i>.