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<p>Since the discovery of the <i>BRCA1</i> and <i>BRCA2</i> (hereafter referred to as <i>BRCA1</i>/<i>2</i>) 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. <i>Brca1</i>/<i>2</i>-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 <i>BRCA1</i>/<i>2</i>-associated cancer. Genetically engineered and patient-derived mouse tumor models have also been instrumental in developing new (combination) therapies for patients with <i>BRCA1</i>/<i>2</i>-mutated cancers and to study mechanisms of therapy resistance. In this Perspective, we highlight the crucial insights into the complex biology of <i>BRCA1</i>/<i>2</i> 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 <i>BRCA1</i>/<i>2</i> and improve the quality of life of mutation carriers.</p>

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Insights from three decades of BRCA1/2 modeling in mice

  • 期刊论文

  • 发表日期：

    2026年1月6日

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  • Julia-Star Darnold,
  • Jos Jonkers

摘要

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.