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Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression.


ABSTRACT: Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, nonlethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression rendered tumor cells more aggressive and increased metastasis. The results translate into a new therapeutic strategy: enhancement of the NAD+/NADH balance through treatment with NAD+ precursors inhibited metastasis in xenograft models, increased animal survival, and strongly interfered with oncogene-driven breast cancer progression in the MMTV-PyMT mouse model. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells, while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression.

SUBMITTER: Santidrian AF 

PROVIDER: S-EPMC3582128 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression.

Santidrian Antonio F AF   Matsuno-Yagi Akemi A   Ritland Melissa M   Seo Byoung B BB   LeBoeuf Sarah E SE   Gay Laurie J LJ   Yagi Takao T   Felding-Habermann Brunhilde B  

The Journal of clinical investigation 20130215 3


Despite advances in clinical therapy, metastasis remains the leading cause of death in breast cancer patients. Mutations in mitochondrial DNA, including those affecting complex I and oxidative phosphorylation, are found in breast tumors and could facilitate metastasis. This study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Specific enhancement of mitochondrial complex I activity inhibited tumor growth and metastasis through regulati  ...[more]

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