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BRCA1 Deficiency Impairs Mitophagy and Promotes Inflammasome Activation and Mammary Tumor Metastasis
- Source :
- Advanced Science, Vol 7, Iss 6, Pp n/a-n/a (2020), Advanced Science
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
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.<br />Breast cancer susceptibility gene 1 (BRCA1) not only negatively regulates mitochondrial fusion but also facilitates stress‐induced fission and mitophagy. BRCA1 deficiency causes oxidative stress and inflammasome activation, which creates a tumor‐associated microenvironment, thereby promoting breast cancer development. This study uncovers the function of BRCA1 in regulating mitophagy and provides a rational approach for treating BRCA1 mutant breast cancer with inflammasome inhibitors.
- Subjects :
- Tumor suppressor gene
General Chemical Engineering
General Physics and Astronomy
Medicine (miscellaneous)
02 engineering and technology
Biology
010402 general chemistry
01 natural sciences
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Metastasis
Mitophagy
medicine
General Materials Science
inflammasomes
lcsh:Science
skin and connective tissue diseases
Protein kinase A
Mammary tumor
Full Paper
General Engineering
AMPK
Inflammasome
Full Papers
BRCA1
021001 nanoscience & nanotechnology
medicine.disease
mitochondrial dynamics
0104 chemical sciences
Cell biology
mitophagy
ATM‐AMPK‐DRP1
lcsh:Q
Mitochondrial fission
0210 nano-technology
medicine.drug
Subjects
Details
- ISSN :
- 21983844
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Advanced Science
- Accession number :
- edsair.doi.dedup.....2efa5be934edcee8efcc713fbe0948d9