J Puppe, M Opdam, PC Schouten, K Jóźwiak, EH Lips, T Severson, M van de Ven, CS Brambillasca, P Bouwman, O van Tellingen, R Bernards, J Wesseling, C Eichler, F Thangarajah, W Malter, GK Pandey, L Ozretić, C Caldas, M van Lohuizen, M Hauptmann, K Rhiem, E Hahnen, HC Reinhardt, R Büttner, P Mallmann, B Schömig-Markiefka, RK Schmutzler, SC Linn, J Jonkers
Clin Cancer Res
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 1) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; 2) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. EXPERIMENTAL DESIGN: EZH2 expression was analyzed in 497 breast cancers using immunohistochemistry 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 to standard anthracyline-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 to single agents. CONCLUSION: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify breast cancer patients that 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.