BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis

Abstract The breast cancer susceptibility gene 1 (BRCA1) is a major tumor suppressor gene and is most frequently mutated in hereditary breast cancer. BRCA1 plays a critical role in many biological processes, especially maintaining genomic stability in the nucleus, yet its role in the cytoplasm remains elusive. Here, it is revealed that BRCA1 maintains a healthy mitochondrial network through regulating mitochondrial dynamics, including fission and fusion. BRCA1 deficiency causes dysfunctional mitochondrial dynamics through increased expression of mitofusin1/2. With mitochondrial stress, BRCA1 is recruited to the mitochondrial outer membrane, where it plays an essential role in maintaining a healthy mitochondrial network. Consequently, BRCA1 deficiency impairs stress‐induced mitophagy through blocking ataxia‐telangiectasia mutated (ATM)‐AMP‐activated protein kinase (AMPK)‐Dynamin‐related protein 1 (DRP1)‐mediated mitochondrial fission and triggers NLRP3 inflammasome activation, which creates a tumor‐associated microenvironment, thereby facilitating tumor proliferation and metastasis. It is further shown that inflammasome inhibition can prevent tumor recurrence and metastasis. This study uncovers an important role of BRCA1 in regulating mitophagy and suggests a therapeutic approach for fighting this deadly disease.