TY - JOUR
T1 - EZH2 is overexpressed in BRCA1-like breast tumors and predictive for sensitivity to high-dose platinum-based chemotherapy
AU - Puppe, Julian
AU - Opdam, Mark
AU - Schouten, Philip C.
AU - Jozwiak, Katarzyna
AU - Lips, Esther
AU - Severson, Tesa
AU - van de Ven, Marieke
AU - Brambillasca, Chiara
AU - Bouwman, Peter
AU - van Tellingen, Olaf
AU - Bernards, Rene
AU - Wesseling, Jelle
AU - Eichler, Christian
AU - Thangarajah, Fabinshy
AU - Malter, Wolfram
AU - Pandey, Gaurav Kumar
AU - Ozretic, Luka
AU - Caldas, Carlos
AU - van Lohuizen, Maarten
AU - Hauptmann, Michael
AU - Rhiem, Kerstin
AU - Hahnen, Eric
AU - Reinhardt, H. Christian
AU - Buttner, Reinhard
AU - Mallmann, Peter
AU - Schomig-Markiefka, Birgid
AU - Schmutzler, Rita
AU - Linn, Sabine
AU - Jonkers, Jos
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85069042646&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-4024
DO - 10.1158/1078-0432.CCR-18-4024
M3 - Article
C2 - 31036541
AN - SCOPUS:85069042646
SN - 1078-0432
VL - 25
SP - 4351
EP - 4362
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -