It is a well-established scientific observation that mammalian cells contain fidelity or watchdog proteins that maintain the correct function of cellular organelles. Over the past several years, the Sirtuin deacetylase family protein Sirt3 has emerged as a mitochondrial fidelity protein that directs energy generation and regulates reactive oxygen species (ROS) scavenging proteins. Genetic deletion of these fidelity proteins has been shown to create a cellular environment that is permissive for the development of cellular damage associated with processes such as aging and breast ductal cell carcinogenesis. In this regard, we have previously shown that mice lacking the mitochondrial Sirtuin-3 (Sirt3) gene develop estrogen receptor (ER+) positive, p53 wild-type, poorly differentiated invasive ductal carcinomas (IDC) (Kim et al., 2010, Cancer Cell), a subtype of malignancy similar to luminal B breast cancer that is predominantly observed in older women. Mice lacking Sirt3 also exhibit increased ROS, including superoxide due to the aberrant acetylation of manganese superoxide dismutase (MnSOD) resulting in decreased enzymatic ROS scavenging activity. In addition, over expressing a mutant deacetylated-mimic MnSOD isoform, which exhibits increased SOD enzymatic activity, reversed the tumor permissive phenotype (Tao et al, 2010, Molecular Cell) observed in breast tumor cells lacking Sirt3.

Finally, in collaboration with Dr. Joe Bass (Corresponding Author, Northwestern University) a link between SIRT3 and the clock proteins, in the form of mitochondrial NAD+ concentrations has been discovered. Specifically, a clock protein loop directs SIRT3, via NAD+ bioavailability, to regulate mitochondrial glycolytic and oxidative metabolism, as well as MnSOD lysine acetylation and detoxification activity. Furthermore, NAD+ supplementation decreased MnSOD acetylation and significantly restored mitochondrial function in circadian mutant mice by a mechanism involving SIRT3 activity (Peek et al., 2013, Science). These results suggest that circadian clock proteins coordinate mitochondrial metabolism, in part via the modulation of protein acetylation, to synchronize metabolic and oxidative pathways with circadian rhythms.

Citation Format: David Gius. SIRT3 is a mitochrondial tumor suppressor in breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN11-03.