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Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer
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Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer
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Journal Article
Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer
2015
Overview
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 inbreast 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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ ATP Binding Cassette Transporter, Subfamily B - genetics
/ ATP Binding Cassette Transporter, Subfamily B - metabolism
/ Breast Neoplasms - drug therapy
/ Breast Neoplasms - metabolism
/ Carcinosarcoma - drug therapy
/ DNA
/ Drug Resistance, Neoplasm - genetics
/ drugs
/ Enzyme Inhibitors - pharmacology
/ Female
/ females
/ Humans
/ Mammary Neoplasms, Experimental - drug therapy
/ Mammary Neoplasms, Experimental - genetics
/ Mammary Neoplasms, Experimental - metabolism
/ mice
/ patients
/ Poly(ADP-ribose) Polymerase Inhibitors
/ Poly(ADP-ribose) Polymerases - metabolism
/ Rodents
/ Tumors
