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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acrylamides / pharmacology
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Animals
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Autophagy
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Autophagy-Related Protein 5
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Brain Neoplasms / metabolism*
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Brain Neoplasms / secondary
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Cell Line, Tumor
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Cell Proliferation
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Cytokines / antagonists & inhibitors
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Cytokines / metabolism
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Disease Progression
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Electron Transport Complex I / biosynthesis
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Electron Transport Complex I / physiology*
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Female
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Gene Knockdown Techniques
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Humans
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Lung Neoplasms / metabolism*
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Lung Neoplasms / secondary
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Mammary Neoplasms, Experimental / metabolism*
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Mammary Neoplasms, Experimental / pathology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred BALB C
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Mice, SCID
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Mitochondria / metabolism
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Multiprotein Complexes
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NAD / metabolism*
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NAD / physiology
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Neoplasm Transplantation
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Niacin / pharmacology
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Niacinamide / pharmacology
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Nicotinamide Phosphoribosyltransferase / antagonists & inhibitors
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Nicotinamide Phosphoribosyltransferase / metabolism
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Piperidines / pharmacology
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Protein Transport
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Proteins / metabolism
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Recombinant Proteins / biosynthesis
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Saccharomyces cerevisiae Proteins / biosynthesis
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Saccharomyces cerevisiae Proteins / physiology*
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TOR Serine-Threonine Kinases
Substances
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ATG5 protein, human
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Acrylamides
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Autophagy-Related Protein 5
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Cytokines
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Microtubule-Associated Proteins
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Multiprotein Complexes
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N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide
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Ndi1 protein, S cerevisiae
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Piperidines
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Proteins
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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NAD
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Niacinamide
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Niacin
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Nicotinamide Phosphoribosyltransferase
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nicotinamide phosphoribosyltransferase, human
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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Electron Transport Complex I