title: Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer.
abstract: Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Linda
authors.initials: L
authors.lastname: Henneman
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Martine H
authors.initials: MH
authors.lastname: van Miltenburg
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Michalak
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Mouse Clinic for Cancer and Aging (MCCA) Transgenic Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Janneke E
authors.initials: JE
authors.lastname: Jaspers
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Anne Paulien
authors.initials: AP
authors.lastname: Drenth
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Renske
authors.initials: R
authors.lastname: de Korte-Grimmerink
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Ewa
authors.initials: E
authors.lastname: Gogola
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Einsteinweg 20, 2333 ZC Leiden, The Netherlands;
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Mouse Clinic for Cancer and Aging (MCCA) Transgenic Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Rahmen
authors.initials: R
authors.lastname: Bin Ali
authors.affiliation: Mouse Clinic for Cancer and Aging (MCCA) Transgenic Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Colin
authors.initials: C
authors.lastname: Pritchard
authors.affiliation: Mouse Clinic for Cancer and Aging (MCCA) Transgenic Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: Huijbers
authors.affiliation: Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; j.jonkers@nki.nl.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002296:Carcinosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016019:Survival Analysis
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000090063:Proto-Oncogene Mas; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: BRCA1; PARP; breast cancer; mouse model; resistance