EZH2 Is Overexpressed in BRCA1 -like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

• Published in: Clinical cancer research 2019-07, Vol.25 (14), p.4351-4362
• Main Authors: Puppe, Julian, Opdam, Mark, Schouten, Philip C, Jóźwiak, Katarzyna, Lips, Esther, Severson, Tesa, van de Ven, Marieke, Brambillasca, Chiara, Bouwman, Peter, van Tellingen, Olaf, Bernards, René, Wesseling, Jelle, Eichler, Christian, Thangarajah, Fabinshy, Malter, Wolfram, Pandey, Gaurav Kumar, Ozretić, Luka, Caldas, Carlos, van Lohuizen, Maarten, Hauptmann, Michael, Rhiem, Kerstin, Hahnen, Eric, Reinhardt, H Christian, Büttner, Reinhard, Mallmann, Peter, Schömig-Markiefka, Birgid, Schmutzler, Rita, Linn, Sabine, Jonkers, Jos
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Enhancer of Zeste Homolog 2 Protein - genetics; Enhancer of Zeste Homolog 2 Protein - metabolism; Female; Humans; Mammary Neoplasms, Animal - drug therapy; Mammary Neoplasms, Animal - genetics; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Mice; Mice, Knockout; Platinum - therapeutic use; Survival Rate; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-4024

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