دورية أكاديمية
Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
| العنوان: | Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer |
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| المؤلفون: | 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 |
| المصدر: | Nature Communications ; volume 10, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-019-08301-2 |
| الإتاحة: | https://doi.org/10.1038/s41467-019-08301-2Test https://www.nature.com/articles/s41467-019-08301-2.pdfTest https://www.nature.com/articles/s41467-019-08301-2Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.B4AAA0EA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-019-08301-2 |
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