Role of Polymerase Gamma Mutations in Breast Tumorigenesis

摘要

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.