One idea of personalized cancer therapy is to identify specific subgroup of cancer patients that will benefit from specific therapeutic strategy. Recently the NCI has proposed a new research emphasis to design rigorous and innovative research strategies to solve specific problems and paradoxes in cancer research identified as the NCI's Provocative Questions. This research proposal addresses one such question How does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In addition, can the pathways that direct life span be used to identify potential molecular biomarkers and targets that can subsequently be used to identify specific groups of malignancies that will respond to targeted anticancer agents? This proposal clearly addresses this question in that we have previously shown that mice lacking mitochondrial Sirt3 gene develop estrogen receptor (ER) positive mammary tumors, a subtype of breast cancer predominantly observed in older women. Clinical data also suggest that there is a subgroup of ER positive luminal B human breast cancers that exhibit partial or complete loss of SIRT3 expression. In the last year the laboratory has made significant progress in delineating the underlying mechanistic relationship between reactive oxygen species (ROS) levels, HIF-1a signaling, and an in vivo phenotype permissive for breast carcinogenesis. Thus, it is proposed that there may be a specific subgroup of breast malignancies where loss of Sirt3 results in increased ROS and HIF1a that are early events in carcinogenesis and as such, agents that scavenge ROS molecules and/or inhibit HIF1a may prove to enhance cancer prevention or treatment. In this grant application we propose that mice lacking Sirt3 are a novel in vivo model in which to investigate the well established connection between decreased SIRT3 levels and ROS, HIF-1a, the Warburg effect, and breast malignancies. We hypothesize that agents thought to scavenge or decrease cellular ROS (O2-.) and/or inhibit HIF-1? activity will prevent tumors in Sirt3 knockout mice.

Public Health Relevance

This research proposal addresses the question of how does the life span of an organism affect the molecular mechanisms of cancer development and can we use our deepening knowledge of aging to enhance prevention or treatment of cancer? In this regard, the Sirt3 knockout mouse is an in vivo murine model that genetically connects the sirtuin aging gene family, cellular metabolism, and mammary ductal cell tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA168292-05
Application #
9114533
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perloff, Marjorie
Project Start
2012-09-21
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
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
Zhu, Yueming; Dean, Angela Elizabeth; Horikoshi, Nobuo et al. (2018) Emerging evidence for targeting mitochondrial metabolic dysfunction in cancer therapy. J Clin Invest 128:3682-3691
Quan, Songhua; Principe, Daniel R; Dean, Angela E et al. (2018) Loss of Sirt2 increases and prolongs a caerulein-induced pancreatitis permissive phenotype and induces spontaneous oncogenic Kras mutations in mice. Sci Rep 8:16501
Zou, Xianghui; Zhu, Yueming; Park, Seong-Hoon et al. (2017) SIRT3-Mediated Dimerization of IDH2 Directs Cancer Cell Metabolism and Tumor Growth. Cancer Res 77:3990-3999
Shi, Han; Deng, Han-Xiang; Gius, David et al. (2017) Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum Mol Genet 26:1915-1926
Traba, Javier; Geiger, Sarah S; Kwarteng-Siaw, Miriam et al. (2017) Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and activation via SIRT3-mediated activation of superoxide dismutase 2. J Biol Chem 292:12153-12164
Traver, Geri; Mont, Stacey; Gius, David et al. (2017) Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 112:578-586
Jablonski, Renea P; Kim, Seok-Jo; Cheresh, Paul et al. (2017) SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31:2520-2532
Yang, Xiaoyan; Park, Seong-Hoon; Chang, Hsiang-Chun et al. (2017) Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest 127:1505-1516
Liu, Guoxiang; Park, Seong-Hoon; Imbesi, Marta et al. (2017) Loss of NAD-Dependent Protein Deacetylase Sirtuin-2 Alters Mitochondrial Protein Acetylation and Dysregulates Mitophagy. Antioxid Redox Signal 26:849-863
Zou, Xianghui; Santa-Maria, Cesar Augusto; O'Brien, Joseph et al. (2016) Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype. Antioxid Redox Signal 25:326-36

Showing the most recent 10 out of 35 publications