EZH2 is overexpressed in BRCA1-like breast tumors and predictive for sensitivity to high-dose platinum-based chemotherapy

Julian Puppe, Mark Opdam, Philip C. Schouten, Katarzyna Jozwiak, Esther Lips, Tesa Severson, Marieke van de Ven, Chiara Brambillasca, Peter Bouwman, Olaf van Tellingen, Rene Bernards, Jelle Wesseling, Christian Eichler, Fabinshy Thangarajah, Wolfram Malter, Gaurav Kumar Pandey, Luka Ozretic, Carlos Caldas, Maarten van Lohuizen, Michael HauptmannKerstin Rhiem, Eric Hahnen, H. Christian Reinhardt, Reinhard Buttner, Peter Mallmann, Birgid Schomig-Markiefka, Rita Schmutzler, Sabine Linn, Jos Jonkers

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4351-4362
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number14
DOIs
StatePublished - 2019
Externally publishedYes

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