Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer
作者： Linda Henneman , Martine H. van Miltenburg , Ewa M. Michalak , Tanya M. Braumuller , Janneke E. Jaspers
关键词: Metaplastic Breast Carcinoma 、 Breast cancer 、 Biology 、 Cancer research 、 Olaparib 、 Mesenchymal stem cell 、 Cell 、 Immunology 、 Poly ADP ribose polymerase 、 Efflux 、 PARP inhibitor
摘要: Metaplastic breast carcinoma (MBC) is a rare histological cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents poly(ADP-ribose) polymerase (PARP) inhibitors, we sought investigate the response BRCA1-deficient PARP inhibitor olaparib. To this end, established genetically engineered mouse model (GEMM) for MBC introducing MET proto-oncogene into BRCA1-associated model, using our novel female GEMM ES cell (ESC) pipeline. In contrast carcinomas, carcinosarcomas resembling show intrinsic resistance olaparib caused increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, could be circumvented another inhibitor, AZD2461, which Pgp substrate. These preclinical findings suggest that patients with may illustrate value GEMM-ESC models human evaluation therapeutics.
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