SIRT3 is a Mitochondrial Tumor Suppressor and Genetic Loss Results in a Murine Model for ER/PR-Positive Mammary Tumors Connecting Metabolism and Carcinogenesis SIRT3 is a Mitochondrial Tumor Suppressor
Annual rept. 1 Sep 2011-31 Aug 2012
VANDERBILT UNIV NASHVILLE TN
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The overarching goal of this proposal is to determine if the mitochondrial sirtuin SIRT3 is a tumor suppressor gene TSG that may be used to 1 establish a murine model to investigate the mechanisms of carcinogenesis in ERPR-positive mammary tumors and 2 determine if SIRT3 may serve as biomarker that correlates with clinically and pathologically significant outcomes including response to therapy, local tumor control, disease free survival, and a new molecular overall survival. Preliminary data from our laboratory demonstrated that 1 Sirt3 knockout mice exhibit decreased mitochondrial integrity and are genomically unstable when exposed to genotoxic agents 2 Sirt3-- MEFs transformed by either Myc or Ras have aberrant intracellular metabolism including increases in glycolysis, superoxide levels, and chromosomal abnormalities 3 MnSOD prevents immortalization of Sirt3-- MEFs by a single oncogene 4 Sirt3 knockout mice develop ERPR-positive mammary tumors and 6 SIRT3 expression is decreased in human breast tumors. Based on these results we initially proposed a hypothesis that longevity genes impact the process of carcinogenesis via the maintenance of mitochondrial integrity and oxidative metabolism. Specifically, loss of sirtuin expression could result in mitochondrial damage and a phenotype permissive for mammary tumors. In this regard, we proposed to i Identify SIRT3 mitochondrial deacetylation targets and determine if these targets are regulated by extracellular stimuli known to activate sirtuin function resveratrol. These targets will subsequently be knocked down siRNA to determine if there is a mechanistic connection between the increase in superoxide and stress-induced genomic instability observed in Sirt3-- cells.
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