Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer and that diabetes may dramatically increase mortality in patients with cancer. Importantly, African-American and Hispanic/Latina women are disproportionately affected by diabetes and its complications. Concurrently, these women have worst outcome from breast cancer. Diabetes and cancer share many risk factors, but potential biologic links between the two diseases are incompletely understood. Our preliminary studies have provided new insights into how high glucose (HG) functions in breast epithelial cells. Exposure of cultured transformed (MCF-7) and normal (MCF-10A) breast epithelial cells to clinically relevant levels of glucose dramatically suppresses the tumor suppressor p53 acetylation, and, consequently, additively promotes tumor cell proliferation and abrogates DNA damage-induced apoptosis. Importantly, activation of nuclear phosphatase PP2Cd plays a role in this process. In addition, we for the first time demonstrate that BRAC1 forms a complex with p300 and p53, and an increased phosphorylation of BRAC1 by DNA damage enhances the recruitment of p53 to p300 and facilitates subsequent p53 acetylation. Upon activation by HG, PP2Cd dephosphorylates BRAC1 and inhibits its up-regulatory effect on p53 acetylation. These results may not only provide explanation for increased epithelial proliferation and tumorigenesis by hyperglycemia, but also increased breast cancer risk by diabetes. Based on these results we hypothesize that hyperglycemia, via a pathway that involved in PP2Cd activation, suppresses the tumor suppressor BRCA1 and p53 function and inhibits DNA damage-induced apoptosis and cell cycle arrest, inducing proliferation in the epithelium and the initiation and development of breast cancer. This hypothesis will be tested in three specific aims: (1) To explore the mechanisms underlying HG-induced PP2Cd activation; (2) To investigate the molecular mechanism by which PP2Cd dephosphorylates BRAC1 and antagonizes p53 acetylation in breast epithelial cells; (3) To characterize the effects of hyperglycemia on the development and chemotherapy of breast cancer in vivo using streptozotocin (STZ)-induced or high fat diet/STZ-induced diabetic nude mice bearing MCF-7 cells and breast cancer specimens from patients with or without diabetes. These studies set the stage for investigating this novel mechanism connecting diabetes and breast cancer with a goal of defining a new pathway and providing additional targets for therapy. Breast cancer in particular affects a large sector of African-American and Hispanic women and constitutes a significant financial burden for the society. Thus, studying the influence of hyperglycemia on oncogenic signaling networks is a novel question with considerable translational implications and would be a significant step in shedding light on this health disparity.

Public Health Relevance

Substantial epidemiological studies suggest that women with diabetes have increased risk of breast cancer and that diabetes may dramatically increase mortality in patients with cancer. This proposal addresses mechanisms connecting diabetes and breast cancer with a goal of defining a new pathway and providing additional targets for therapy. Breast cancer and diabetes constitute a major financial burden for the American society and every possible effort including a full understanding of the molecular basis of these diseases should be made to diminish the financial impact on society and to improve the quality of life of those who suffer from these diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Enhancement Award (SC1)
Project #
5SC1CA200517-04
Application #
9514050
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Ojeifo, John O
Project Start
2015-07-21
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Charles R. Drew University of Medicine & Science
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
785877408
City
Los Angeles
State
CA
Country
United States
Zip Code
90059
Liu, Kun; Hao, Qiongyu; Wei, Jie et al. (2018) MicroRNA-19a/b-3p protect the heart from hypertension-induced pathological cardiac hypertrophy through PDE5A. J Hypertens 36:1847-1857
Elshimali, Yahya I; Wu, Yong; Khaddour, Hussein et al. (2018) Optimization Of Cancer Treatment Through Overcoming Drug Resistance. J Cancer Res Oncobiol 1:
Wu, Yong; Yu, Xiaoting; Yi, Xianghua et al. (2017) Aberrant Phosphorylation of SMAD4 Thr277-Mediated USP9x-SMAD4 Interaction by Free Fatty Acids Promotes Breast Cancer Metastasis. Cancer Res 77:1383-1394
Wu, Yong; Lee, Sangkyu; Bobadilla, Selene et al. (2017) High glucose-induced p53 phosphorylation contributes to impairment of endothelial antioxidant system. Biochim Biophys Acta Mol Basis Dis 1863:2355-2362
Dong, Yunzhou; Fernandes, Conrad; Liu, Yanjun et al. (2017) Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis. Diab Vasc Dis Res 14:14-23
Chung, Seyung S; Wu, Yong; Okobi, Quincy et al. (2017) Proinflammatory Cytokines IL-6 and TNF-? Increased Telomerase Activity through NF-?B/STAT1/STAT3 Activation, and Withaferin A Inhibited the Signaling in Colorectal Cancer Cells. Mediators Inflamm 2017:5958429
Dong, Yunzhou; Cai, Xue; Wu, Yong et al. (2017) Insights from Genetic Model Systems of Retinal Degeneration: Role of Epsins in Retinal Angiogenesis and VEGFR2 Signaling. J Nat Sci 3:
Zhang, Yu-Yao; Li, Chao; Yao, Gao-Feng et al. (2017) Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ER?/HGF/Met Pathway. Diabetes 66:1535-1547
Wu, Yong; Dong, Yunzhou; Duan, Shengzhong et al. (2017) Corrigendum to ""Metabolic Syndrome, Inflammation, and Cancer"". Mediators Inflamm 2017:6598540
Wu, Yong; Dong, Yunzhou; Duan, Shengzhong et al. (2017) Metabolic Syndrome, Inflammation, and Cancer. Mediators Inflamm 2017:8259356

Showing the most recent 10 out of 15 publications