A fundamental observation in oncology is that the rate of malignancies increases significantly as a function of age suggesting a potential mechanistic link between the cellular process governing longevity and the development of cancers. In this regard, the genes that play a critical role in longevity (or aging) have recently been characterized in Saccharomyces cerevisiae and C. elegans and the human homologs of these genes are referred to as the Sirtuin gene family. Thus, we hypothesized that the sirtuin genes might function as fidelity genes and loss sirtuin function, which might occur during aging, would create cellular environment permissive for age related illness including carcinogenesis. To address this idea we constructed mice four years ago that have the mitochondrial localized SIRT3 protein genetically deleted. Our laboratory has recently shown that these mice develop estrogen and progesterone receptor (ER/PR) positive mammary tumors that are a subtype of cancer commonly observed in older women. The results of these experiments suggest that SIRT3 is the first identified genomic expressed, mitochondrial localized tumor suppressor (TS) and also suggests a genetic relationship between a mitochondrial aging gene and a cellular environment or phenotype permissive for development of mammary tumors. It has also been shown that intracellular reactive oxygen species (ROS), as well as the mitochondrial superoxide dismutase gene (MnSOD) - the primary superoxide scavenging protein - play a role in aging and carcinogenesis. In this regard, our preliminary results demonstrated altered superoxide in our SIRT3 knockout mice. Thus, we hypothesize that agents thought to prevent the cellular effects of aging and the accumulation of intracellular ROS, such as CR, will be prevent tumors in the SIRT3 knockout mice. In addition, use a series of immunohistochemical staining to characterize the pathological, histology, and redox changes in the murine ductal cells to begin to identify the potential underlying in vivo mechanism of carcinogenic permissive phenotype observed in the SIRT3 knockout mice.

Public Health Relevance

The overarching theme of this proposal is based on one of the fundamental observations in oncology showing that the rate of malignancies increases significantly with age. Recently, it was shown that the Sirtuin gene family may determine aging (longevity). Thus, we hypothesize a genetic and biochemical relationship between the mitochondrial sirtuin, SIRT3, metabolism, and ER/PR positive breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA152799-03
Application #
8547783
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$297,722
Indirect Cost
$105,022
Name
Northwestern University at Chicago
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Ozden, Ozkan; Park, Seong-Hoon; Wagner, Brett A et al. (2014) SIRT3 deacetylates and increases pyruvate dehydrogenase activity in cancer cells. Free Radic Biol Med 76:163-72
Desouki, Mohamed Mokhtar; Doubinskaia, Irina; Gius, David et al. (2014) Decreased mitochondrial SIRT3 expression is a potential molecular biomarker associated with poor outcome in breast cancer. Hum Pathol 45:1071-7
Tao, Randa; Vassilopoulos, Athanassios; Parisiadou, Loukia et al. (2014) Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis. Antioxid Redox Signal 20:1646-54
Vassilopoulos, Athanassios; Pennington, J Daniel; Andresson, Thorkell et al. (2014) SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress. Antioxid Redox Signal 21:551-64
Peek, Clara Bien; Affinati, Alison H; Ramsey, Kathryn Moynihan et al. (2013) Circadian clock NAD+ cycle drives mitochondrial oxidative metabolism in mice. Science 342:1243417
Zhu, Yueming; Yan, Yufan; Gius, David R et al. (2013) Metabolic regulation of Sirtuins upon fasting and the implication for cancer. Curr Opin Oncol 25:630-6
Zhang, Hui; Park, Seong-Hoon; Pantazides, Brooke G et al. (2013) SIRT2 directs the replication stress response through CDK9 deacetylation. Proc Natl Acad Sci U S A 110:13546-51
Jacobus, James A; Duda, Chester G; Coleman, Mitchell C et al. (2013) Low-dose radiation-induced enhancement of thymic lymphomagenesis in Lck-Bax mice is dependent on LET and gender. Radiat Res 180:156-65
Park, Seong-Hoon; Ozden, Ozkan; Jiang, Haiyan et al. (2011) Sirt3, Mitochondrial ROS, Ageing, and Carcinogenesis. Int J Mol Sci 12:6226-39
Kim, Hyun-Seok; Vassilopoulos, Athanassios; Wang, Rui-Hong et al. (2011) SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell 20:487-99

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