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

Author

Listed:
  • Stefano Annunziato

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Julian R. de Ruiter

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Linda Henneman

    (The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Chiara S. Brambillasca

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Catrin Lutz

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • François Vaillant

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Federica Ferrante

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Anne Paulien Drenth

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Eline van der Burg

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Bjørn Siteur

    (The Netherlands Cancer Institute)

  • Bas van Gerwen

    (The Netherlands Cancer Institute)

  • Roebi de Bruijn

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Martine H. van Miltenburg

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Ivo J. Huijbers

    (The Netherlands Cancer Institute)

  • Marieke van de Ven

    (The Netherlands Cancer Institute)

  • Jane E. Visvader

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Geoffrey J. Lindeman

    (Walter and Eliza Hall Institute of Medical Research
    University of Medicine
    Royal Melbourne Hospital and Peter MacCallum Cancer Centre)

  • Lodewyk F. A. Wessels

    (Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

  • Jos Jonkers

    (The Netherlands Cancer Institute
    Cancer Genomics Netherlands, The Netherlands Cancer Institute
    The Netherlands Cancer Institute)

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.

Suggested Citation

  • 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, 2019. "Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08301-2
    DOI: 10.1038/s41467-019-08301-2
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    Cited by:

    1. Dario Zimmerli & Chiara S. Brambillasca & Francien Talens & Jinhyuk Bhin & Renske Linstra & Lou Romanens & Arkajyoti Bhattacharya & Stacey E. P. Joosten & Ana Moises Silva & Nuno Padrao & Max D. Welle, 2022. "MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Miguel Vizoso & Colin E. J. Pritchard & Lorenzo Bombardelli & Bram van den Broek & Paul Krimpenfort & Roderick L. Beijersbergen & Kees Jalink & Jacco van Rheenen, 2022. "A doxycycline- and light-inducible Cre recombinase mouse model for optogenetic genome editing," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Julia M. Houthuijzen & Roebi Bruijn & Eline Burg & Anne Paulien Drenth & Ellen Wientjens & Tamara Filipovic & Esme Bullock & Chiara S. Brambillasca & Emilia M. Pulver & Marja Nieuwland & Iris Rink & F, 2023. "CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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