Journal article
Mechanisms of therapy resistance in patient-derived xenograft models of brca1-deficient breast cancer
P Ter Brugge, P Kristel, E Van Der Burg, U Boon, M De Maaker, E Lips, L Mulder, J De Ruiter, C Moutinho, H Gevensleben, E Marangoni, I Majewski, K Jozwiak, W Kloosterman, M Van Roosmalen, K Duran, F Hogervorst, N Turner, M Esteller, E Cuppen Show all
Journal of the National Cancer Institute | OXFORD UNIV PRESS INC | Published : 2016
DOI: 10.1093/jnci/djw148
Abstract
Background: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1- mutated and BRCA1-methylated triple-negative breast cancer. Methods: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time..
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Awarded by European Commission
Funding Acknowledgements
This research was supported by grants from the Dutch Cancer Society (NKI 2011-5197 and EMCR 2014-7048); the Netherlands Organization for Scientific Research (NWO-NGI Zenith 93512009 and NWO-ZonMW Vici 91814643); the Eurocan Platform network of excellence, funded by the EU Seventh Framework Programme; the CombatCancer synergy project, funded by the European Research Council; and the Cancer Genomics Netherlands gravitation programme and Cancer Systems Biology Center (CSBC), funded by the NWO.