The Role of Polymerase Gamma Mutations in Breast Tumorigenesis
Annual summary rept. 1 Aug 2009-31 Dec 2010
HEALTH RESEARCH INC BUFFALO NY
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Mutation in polymerase gamma POLG have led to depletion of mitochondrial DNA mtDNA and mutations in mtDNA. This proposal seeks to determine the effect of POLG mutations on tumorigenesis of breast cancer by altering mtDNA. A mutant POLG was over expressed in MCF7 transformed, non-invasive breast epithelial cells under the control of a tetracycline responsive promoter. Mutations in POLG led to depletion of mtDNA which then resulted in decreased mitochondrial respiratory activity, decreased inner mitochondrial membrane potential, increased levels of reactive oxygen species ROS. These alterations in mitochondrial function led to increased in vitro invasion, suggesting that shifting intracellular metabolism away from mitochondrial respiration by mtDNA depletion leads to enhanced tumorigenesis. Interestingly, the invasiveness of the cell was reverted when the mutant POLG gene was turned off and mtDNA returned to normal. Genetic alterations within the cell, including nicroRNA and mRNA expression were found when cells were expressing a mutant POLG. Furthermore, treatment with a methylation inhibitor restored POLG expression and mitochondrial function in breast cancer cells. Taken together, this report shows that POLG mutations are causing important metabolic genetic alterations that may play a role in breast cancer.
- Medicine and Medical Research