Epidemiological studies have established a correlation between Type 2 diabetes and increased cancer risk and prognosis. Breast cancer is one of the most common cancers occurring in women. In women with Type 2 diabetes breast cancer is more common and has a worse prognosis, independent of obesity. The mechanisms involved in the increased cancer risk in Type 2 diabetes have not been defined. Determining the mechanisms involved in this process requires the use of animal models that can be manipulated to study the role of the hyperinsulinemia and the insulin receptors (IRs) and insulin-like growth factor-1 receptors (IGF-1Rs) that mediate insulin's effect. We have generated a mouse model of Type 2 diabetes, by introducing a dominant-negative IGF-1R in skeletal muscle that initially leads to severe insulin resistance, followed by the development of Type 2 diabetes. The mice are not obese and this enables us to study the factors related to Type 2 diabetes without the confounding factors involved in obesity. The mammary glands of the diabetic mice have more extensive epithelial growth compared to non-diabetic mice. Induction of mammary tumors by DMBA and the PyVmT oncogene in the diabetic mice resulted in an increased incidence and more aggressive behavior of the tumors compared to the control non-diabetic mice. We hypothesize that the hyperinsulinemia is the cause of the increase in tumor development and that the effect is mediated via the insulin receptors (and IR/IGF-IR hybrid receptors) in the mammary epithelium and in the tumors that develop. We propose to: 1. Define the exact mechanisms causing the increased growth of mammary epithelial cells in the diabetic mice, 2. Examine the mammary epithelium and the tumors for the type of insulin and IGF- 1 receptors expressed, 3. Determine whether the increased tumor incidence is associated with larger tumors and increased metastases, 4. Determine which receptors mediate these events and the signaling pathways involved, 5. Knock-down the IRs and IGF-1Rs in cancer cells and the diabetic mice to determine the effect on tumorigenesis and metastases. 6. Determine whether reversal of the insulin resistance and hyperinsulinemia affects tumor development growth and metastases The results of these studies will provide further insights into our understanding of the factors involved in the increased risk of breast cancer in diabetes and may lead to new opportunities for targeted therapy.

Public Health Relevance

The results of these studies will provide further insights into our understanding of the factors involved in the increased risk of breast cancer in diabetes and may lead to new opportunities for targeted therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Wang, Wendy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
Zip Code
Alikhani, N; Ferguson, R D; Novosyadlyy, R et al. (2013) Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model. Oncogene 32:961-7
Gallagher, E J; Fierz, Y; Vijayakumar, A et al. (2012) Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia. Oncogene 31:3213-22
Vaitheesvaran, B; LeRoith, D; Kurland, I J (2010) MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity. Diabetologia 53:2224-32
Fierz, Yvonne; Novosyadlyy, Ruslan; Vijayakumar, Archana et al. (2010) Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59:686-93
Cannata, Dara; Lann, Danielle; Wu, Yingjie et al. (2010) Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology 151:5751-61
Fierz, Yvonne; Novosyadlyy, Ruslan; Vijayakumar, Archana et al. (2010) Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes. Endocr Relat Cancer 17:941-51
Vijayakumar, Archana; Novosyadlyy, Ruslan; Wu, Yingjie et al. (2010) Biological effects of growth hormone on carbohydrate and lipid metabolism. Growth Horm IGF Res 20:1-7
Novosyadlyy, R; Vijayakumar, A; Lann, D et al. (2009) Physical and functional interaction between polyoma virus middle T antigen and insulin and IGF-I receptors is required for oncogene activation and tumour initiation. Oncogene 28:3477-86
Wu, Yingjie; Sun, Hui; Yakar, Shoshana et al. (2009) Elevated levels of insulin-like growth factor (IGF)-I in serum rescue the severe growth retardation of IGF-I null mice. Endocrinology 150:4395-403