Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-08301-2
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Funding
- Victorian Government, Australia
- SURF Cooperative [e-infra160136]
- Oncode Institute
- Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL))
- Netherlands Organization for Scientific Research (NWO: Cancer Systems Biology Center (CSBC))
- Netherlands Organization for Scientific Research (NWO: Netherlands Genomics Initiative (NGI)) [93512009, 91814643]
- European Research Council (ERC Synergy project CombatCancer)
- National Roadmap grant for Large-Scale Research Facilities from NWO
- National Health and Medical Research Council (Australia) [1113133, 1078730, 1102742]
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BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.
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