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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Stefano Annunziato, Julian R. de Ruiter, Linda Henneman, Chiara S. Brambillasca, Catrin Lutz, François Vaillant, Federica Ferrante, Anne Paulien Drenth, Eline van der Burg, Bjørn Siteur, Bas van Gerwen, Roebi de Bruijn, Martine H. van Miltenburg, Ivo J. Huijbers, Marieke van de Ven, Jane E. Visvader, Geoffrey J. Lindeman, Lodewyk F. A. Wessels, Jos Jonkers

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. More... »

PAGES

397

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-019-08301-2

    DOI

    http://dx.doi.org/10.1038/s41467-019-08301-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111624059

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30674894


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