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Updated: Apr 8, 2026
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer
Linda Henneman1, Martine H van Miltenburg1, Ewa M Michalak1
1Division of Molecular Pathology and Cancer Genomics Centre, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
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.
Insights
Metaplastic breast carcinoma (MBC) with BRCA1 defects shows resistance to olaparib due to P-glycoprotein. Alternative PARP inhibitors like AZD2461 may overcome this resistance in BRCA1-deficient MBC.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metaplastic breast carcinoma (MBC) is rare, aggressive, and often linked to BRCA1 defects.
- BRCA1 deficiency typically sensitizes tumors to DNA-damaging agents and PARP inhibitors.
Purpose of the Study:
- To investigate the efficacy of the PARP inhibitor olaparib in BRCA1-deficient MBC.
- To evaluate genetically engineered mouse models (GEMMs) for studying MBC therapeutics.
Main Methods:
- Established a GEMM for BRCA1-deficient MBC using MET proto-oncogene and a BRCA1-associated model.
- Assessed tumor response to olaparib and identified mechanisms of resistance.
- Tested an alternative PARP inhibitor, AZD2461, to circumvent resistance.
Main Results:
- BRCA1-deficient MBC mouse models exhibited intrinsic resistance to olaparib.
- Increased P-glycoprotein (Pgp) drug efflux was identified as the resistance mechanism.
- The PARP inhibitor AZD2461, a poor Pgp substrate, effectively circumvented olaparib resistance.
Conclusions:
- BRCA1-deficient MBC may be intrinsically resistant to olaparib due to Pgp-mediated drug efflux.
- AZD2461 represents a potential therapeutic strategy for BRCA1-associated MBC.
- GEMM-ESC models are valuable for preclinical evaluation of novel cancer therapeutics.
