Puppe, Julian, Opdam, Mark, Schouten, Philip C., Jozwiak, Katarzyna, Lips, Esther, Severson, Tesa, van de Ven, Marieke, Brambillasca, Chiara, Bouwman, Peter ORCID: 0000-0002-9252-5896, van Tellingen, Olaf ORCID: 0000-0002-1037-6269, Bernards, Rene, Wesseling, Jelle, Eichler, Christian, Thangarajah, Fabinshy, Malter, Wolfram, Pandey, Gaurav Kumar, Ozretic, Luka, Caldas, Carlos ORCID: 0000-0003-3547-1489, van Lohuizen, Maarten, Hauptmann, Michael ORCID: 0000-0001-8539-0148, Rhiem, Kerstin, Hahnen, Eric, Reinhardt, H. Christian, Buettner, Reinhard, Mallmann, Peter, Schoemig-Markiefka, Birgid, Schmutzler, Rita, Linn, Sabine and Jonkers, Jos ORCID: 0000-0002-9264-9792 (2019). EZH2 Is Overexpressed in BRCA1-like Breast Tumors and Predictive for Sensitivity to High-Dose Platinum-Based Chemotherapy. Clin. Cancer Res., 25 (14). S. 4351 - 4363. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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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. Weclassified 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 platinumbased chemotherapy compared with standard anthracyclinebased 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 BRCA1associated 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Puppe, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Opdam, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schouten, Philip C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jozwiak, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lips, EstherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Severson, TesaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Ven, MariekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambillasca, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouwman, PeterUNSPECIFIEDorcid.org/0000-0002-9252-5896UNSPECIFIED
van Tellingen, OlafUNSPECIFIEDorcid.org/0000-0002-1037-6269UNSPECIFIED
Bernards, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wesseling, JelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichler, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thangarajah, FabinshyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malter, WolframUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pandey, Gaurav KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldas, CarlosUNSPECIFIEDorcid.org/0000-0003-3547-1489UNSPECIFIED
van Lohuizen, MaartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hauptmann, MichaelUNSPECIFIEDorcid.org/0000-0001-8539-0148UNSPECIFIED
Rhiem, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahnen, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mallmann, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoemig-Markiefka, BirgidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linn, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jonkers, JosUNSPECIFIEDorcid.org/0000-0002-9264-9792UNSPECIFIED
URN: urn:nbn:de:hbz:38-135079
DOI: 10.1158/1078-0432.CCR-18-4024
Journal or Publication Title: Clin. Cancer Res.
Volume: 25
Number: 14
Page Range: S. 4351 - 4363
Date: 2019
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HISTONE METHYLTRANSFERASE EZH2; CELL FATE; GENE-EXPRESSION; HOMOLOGOUS RECOMBINATION; CANCER DEVELOPMENT; ESTROGEN-RECEPTOR; DOWN-REGULATION; PROTEIN EZH2; REPAIR; CONTRIBUTESMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13507

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