Abstract
Since the discovery of the BRCA1 and BRCA2 (hereafter referred to as BRCA1/2) hereditary breast and ovarian cancer genes three decades ago, genetically engineered and patient-derived mouse models have been instrumental in advancing our understanding of BRCA1/2 biology, particularly their roles in normal development, tumor suppression and therapy response. Brca1/2-mutant mouse models and derivative cell lines have facilitated in vivo dissection of BRCA1/2 functions and identification of the cellular origin and (epi)genetic drivers of BRCA1/2-associated cancer. Genetically engineered and patient-derived mouse tumor models have also been instrumental in developing new (combination) therapies for patients with BRCA1/2-mutated cancers and to study mechanisms of therapy resistance. In this Perspective, we highlight the crucial insights into the complex biology of BRCA1/2 these models have afforded and emphasize those aspects that remain to be elucidated. We also propose next-generation mouse models to further advance our understanding of BRCA1/2 and improve the quality of life of mutation carriers.
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Acknowledgements
We apologize to those authors whose work could not be cited due to space constraints. Research at the Netherlands Cancer Institute is supported by international grants from the Dutch Cancer Society (KWF) and the Dutch Ministry of Health, Welfare and Sport. Research in the Jonkers laboratory is funded by the Oncode Institute, the Dutch Cancer Society (grants 14516 and 14949) and the Swiss National Science Foundation (grant 320030M_219453).
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Darnold, JS., Jonkers, J. Insights from three decades of BRCA1/2 modeling in mice. Nat Genet (2026). https://doi.org/10.1038/s41588-025-02448-z
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DOI: https://doi.org/10.1038/s41588-025-02448-z
