Accession Number : ADA536465


Title :   Role of Polymerase Gamma Mutations in Breast Tumorigenesis


Descriptive Note : Annual summary rept. 1 Aug 2009-31 Jul 2010


Corporate Author : HEALTH RESEARCH INC BUFFALO NY


Personal Author(s) : Owens, Kjerstin M ; Singh, Keshav K


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a536465.pdf


Report Date : Aug 2010


Pagination or Media Count : 27


Abstract : 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 microRNA and mRNA expression were found when cells were expressing a mutant POLG. Taken together, this report shows that POLG mutations are causing important metabolic and genetic alterations that may playa role in breast cancer.


Descriptors :   *MITOCHONDRIA , *METABOLISM , *BREAST CANCER , *DEOXYRIBONUCLEIC ACIDS , MUTATIONS , IN VITRO ANALYSIS , OXYGEN , GAMMA RAYS , RESPIRATORY SYSTEM , CELLS(BIOLOGY) , TETRACYCLINES , MAMMARY GLANDS , NEOPLASMS , POLYMERIZATION , MEMBRANES(BIOLOGY) , FUNCTIONS , DEPLETION


Subject Categories : Biochemistry
      Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE