American Association for Cancer Research
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Figure S1 from EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy

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posted on 2023-03-31, 21:08 authored by Julian Puppe, Mark Opdam, Philip C. Schouten, Katarzyna Jóźwiak, Esther Lips, Tesa Severson, Marieke van de Ven, Chiara Brambillasca, Peter Bouwman, Olaf van Tellingen, René Bernards, Jelle Wesseling, Christian Eichler, Fabinshy Thangarajah, Wolfram Malter, Gaurav Kumar Pandey, Luka Ozretić, Carlos Caldas, Maarten van Lohuizen, Michael Hauptmann, Kerstin Rhiem, Eric Hahnen, H. Christian Reinhardt, Reinhard Büttner, Peter Mallmann, Birgid Schömig-Markiefka, Rita Schmutzler, Sabine Linn, Jos Jonkers

Immunohistological stainings of breast tumors for EZH2 (representative examples of used antibodies)

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Else Kröner-Fresenius Stiftung

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ARTICLE ABSTRACT

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. 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. 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. 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.

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