Julian Puppe 1,2,3 , Mark Opdam 4 , Rita Schmutzler 3 , Sabine Linn 4 , Jos Jonkers 4,3 , Philip C Schouten 4 , Katarzyna Jóźwiak 5 , Esther Lips 4 , Tesa Severson 4 , Marieke van de Ven 4,6 , Chiara Brambillasca 4,6 , Peter Bouwman 4,6 , Olaf van Tellingen 7 , René Bernards 6,8 , Jelle Wesseling 4 , Christian Eichler 2 , Fabinshy Thangarajah 2 , Wolfram Malter 2 , Gaurav Kumar Pandey 6,9 , Luka Ozretić 10 , Carlos Caldas 11 , Maarten van Lohuizen 6,9 , Michael Hauptmann 5 , Kerstin Rhiem 3 , Eric Hahnen 3 , H Christian Reinhardt 12 , Reinhard Büttner 10 , Peter Mallmann 2 , Birgid Schömig-Markiefka 10 Show Affiliations »
Abstract
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 (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors. EXPERIMENTAL DESIGN: EZH2 expression was analyzed in 497 breast cancers using IHC 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 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 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 with single agents. CONCLUSIONS: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers. EZH2 overexpression can identify patients with breast cancer who 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. ©2019 American Association for Cancer Research.
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 (i) EZH2 is overexpressed in human BRCA1-deficient breast tumors and might predict sensitivity to DSB-inducing drugs; (ii) EZH2 inhibition potentiates cisplatin efficacy in Brca1-deficient murine mammary tumors . EXPERIMENTAL DESIGN: EZH2 expression was analyzed in 497 breast cancers using IHC 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 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 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 with single agents. CONCLUSIONS: Our findings demonstrate that EZH2 is expressed at significantly higher levels in BRCA1-deficient breast cancers . EZH2 overexpression can identify patients with breast cancer who 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. ©2019 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
Year: 2019
PMID： 31036541 DOI： 10.1158/1078-0432.CCR-18-4024
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531