BRCA1-mutant breast cancers are associated with poor survival highlighting the need for novel treatment options. In the present study, we show that the Polycomb-group protein EZH2 is significantly higher expressed in breast tumors with a BRCA1-mutation, BRCA1-promoter methylation or a BRCA1-like DNA Copy Number Profile indicating that BRCA1 loss is associated with high EZH2 expression levels. Importantly, EZH2 overexpression can identify breast cancer patients that benefit significantly from intensified DSB-inducing platinum-based chemotherapy. Moreover, pharmaceutical inhibition of EZH2 improves the antitumor effect of platinum drugs in Brca1-deficient breast tumors in vivo. These data indicates that EZH2 is a promising anti-cancer target in BRCA1-associated breast tumors and could be used as a predictive biomarker to categorize patients according to their likelihood to benefit from intensified DSB-inducing platinum-based chemotherapy independent of BRCA1-like status.
Puppe J, Opdam M, Schouten PC, Jóźwiak K, Lips EH, Severson T, van de Ven M, Brambillasca CS, Bouwman P, van Tellingen O, Bernards R, Wesseling J, Eichler C, Thangarajah F, Malter W, Pandey GK, Ozretić L, Caldas C, van Lohuizen M, Hauptmann M, Rhiem K, Hahnen E, Reinhardt HC, Büttner R, Mallmann P, Schömig-Markiefka B, Schmutzler RK, Linn SC, Jonkers J.Clin Cancer Res. 2019 Apr 29. pii: clincanres.4024.2018. doi: 10.1158/1078-0432.CCR-18-4024. [Epub ahead of print]