BRCA1 Mutations in Cancer: Coordinating Deficiencies in Homologous Recombination with Tumorigenesis
- 3 August 2020
- journal article
- review article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 80 (21), 4601-4609
- https://doi.org/10.1158/0008-5472.can-20-1830
Abstract
Cancers that arise from BRCA1 germline mutations are deficient for homologous recombination (HR) DNA repair and are sensitive to DNA damaging agents such as platinum and PARP inhibitors (PARPi). In vertebrate organisms, knockout of critical HR genes including BRCA1 and BRCA2 is lethal because HR is required for genome replication. Thus, cancers must develop strategies to cope with loss of HR activity. Furthermore, as established tumors respond to chemotherapy selection pressure, additional genetic adaptations transition cancers to an HR-proficient state. In this review, we discuss biological mechanisms that influence the ability of BRCA1-mutant cancers to perform HR. Furthermore, we consider how the HR status fluctuates throughout the cancer life course, from tumor initiation to the development of therapy refractory disease.Keywords
Funding Information
- NIH (R01CA214799)
- American Cancer Society (PF-19-097-01-DMC)
- Ovarian Cancer Research Alliance (597484, T32 CA009035)
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