Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
- Author(s)
- Annunziato, S; de Ruiter, JR; Henneman, L; Brambillasca, CS; Lutz, C; Vaillant, F; Ferrante, F; Drenth, AP; van der Burg, E; Siteur, B; van Gerwen, B; de Bruijn, R; van Miltenburg, MH; Huijbers, IJ; van de Ven, M; Visvader, JE; Lindeman, GJ; Wessels, LFA; Jonkers, J;
- Details
- Publication Year 2019-01-23,Volume 10,Issue #1,Page 397
- Journal Title
- Nature Communications
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- Springer Nature
- Research Division(s)
- Cancer Biology And Stem Cells
- PubMed ID
- 30674894
- Publisher's Version
- https://doi.org/10.1038/s41467-019-08301-2
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-08301-2- NHMRC Grants
- NHMRC/113133, NHMRC/1078730, NHMRC/1102742,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-03-13 08:04:11
Last Modified: 2019-03-13 10:02:01