Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer

• Published in: Nature communications Vol. 10; no. 1; p. 397
• Main Authors: Annunziato, Stefano, de Ruiter, Julian R., Henneman, Linda, Brambillasca, Chiara S., Lutz, Catrin, Vaillant, François, Ferrante, Federica, Drenth, Anne Paulien, van der Burg, Eline, Siteur, Bjørn, van Gerwen, Bas, de Bruijn, Roebi, van Miltenburg, Martine H., Huijbers, Ivo J., van de Ven, Marieke, Visvader, Jane E., Lindeman, Geoffrey J., Wessels, Lodewyk F. A., Jonkers, Jos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/107; 13/44; 38/23; 38/91; 631/337/1427; 631/337/4041/3196; 631/61/17/1511; 631/67/1347; 631/67/70; 64/110; 64/60; Animal models; Animals; BRCA1 protein; BRCA1 Protein - genetics; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Carcinogenesis - genetics; Cell Transformation, Neoplastic - genetics; Collagen Type I - genetics; CRISPR; Deoxyribonucleic acid; Disruption; DNA; DNA Copy Number Variations - genetics; Embryo cells; Embryonic Stem Cells; Female; Gene disruption; Gene Expression Regulation, Neoplastic - genetics; Gene Regulatory Networks; Genes; Genetic engineering; HEK293 Cells; Humanities and Social Sciences; Humans; Inhibition; Iterative methods; Mammary Neoplasms, Animal - genetics; Mcl-1 protein; Mice; Mice, Transgenic; multidisciplinary; Mutation; Myc protein; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; PTEN protein; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Transcriptome; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08301-2

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. It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.