David R Gius

Research Interests: Our laboratory concentrates its efforts into the investigation of the mechanistic connection between aging, cellular and/or mitochondrial metabolism, and carcinogenesis focusing on the Sirtuin gene family. To address this idea, over the past five years, we have constructed mice that have the three primary (Sirt1-3) sirtuins genetically deleted. The mice that lack Sirt1 (Wang et al., 2009, Cancer Cell), Sirt2 (Kim et al., 2011, Cancer Cell), and Sirt3 (Kim et al., 2010, Cancer Cell) each develop breast cancer, as well as other types of malignancies to varying degrees, and the levels of SIRT1-3 are also decreased in human cancer samples, as compared to normal tissues. In addition, the mechanism connecting the tumor permissive phenotype and the aberrant regulation of mitochondrial ROS, at least in part, in the Sirt3 knockout mouse has recently been published (Tao et al., 2010, Molecular Cell). Thus, based on these results it seems clear that the primary sirtuin deacetylase proteins are tumor suppressor in several breast cancers as well as to a lesser extent in several other human malignancies. These results seemed logical, since human sirtuins are the human homologs for the yeast and C. elegans longevity genes, and breast cancers have one of the strongest correlations to age. Thus, it is proposed that the primary sirtuin family knockout mice may present a novel group of models to establish, validate, and investigate the well established connection between aging, metabolism, and cancer. These murine models are also used to pursue the laboratories interest and the identification and validation of chemopreventative agents and we currently have a DOD and R01 grants to pursue this for luminal B breast malignancies. Finally, the laboratory has a series of murine in vivo and in vitro models to mechanistically connect Sirt2 and Sirt3 to cancers of the breast, pancreas, liver, and lung that are currently be used.