Determining how insulin and the insulin receptor (IR) signaling promote mammary tumor growth and metastases is critical for our understanding of the association between obesity, type 2 diabetes (T2D) and breast cancer. Obesity and T2D are associated with an increased risk of breast cancer metastasis, recurrence, resistance to therapy and cancer-related mortality, particularly in triple negative and HER2 overexpressing cancers. While there are many metabolic changes in these individuals, endogenous hyperinsulinemia is common to obesity and T2D, and has been independently correlated with a worse prognosis in women with breast cancer. Furthermore, increased IR expression and phosphorylation in human breast cancer specimens is associated with a worse prognosis. To determine insulin's effects on mammary tumor growth, we have studied a mouse model of hyperinsulinemia in isolation from obesity and the other metabolic abnormalities associated with obesity. These hyperinsulinemic mice developed larger primary mammary tumors, and more metastases than mice with normal insulin concentrations. We found that these tumors had increased IR phosphorylation in addition to greater expression of c-myc, vimentin, MMP-9 and miR-222. Therefore, we hypothesize that endogenous hyperinsulinemia, signaling through the IR increases the growth and metastases of triple negative and HER2 overexpressing breast cancers by altering their phenotype. In this proposal we aim to: 1. Determine if the insulin receptor is the key receptor mediating the effect of hyperinsulinemia on mammary tumor growth and metastases. 2. Define the molecular mechanisms through which hyperinsulinemia promotes tumor metastases. We will achieve these aims by using two mouse models of hyperinsulinemia, a non-obese mouse model with isolated hyperinsulinemia, and an obese mouse model will hyperinsulinemia and the other metabolic changes that occur in obesity. We will silence the IR in murine and human triple negative breast cancer cell lines. Using a mammary epithelial specific knockout of the IR, we will examine whether the effects of hyperinsulinemia on mammary tumor growth and metastases are mediated through the IR. Secondly, we will examine the effect of hyperinsulinemia and inhibiting IR signaling on the primary tumor phenotype, including mesenchymal markers and the size of the tumor initiating cell population. We will inhibit c-myc to determine if c-myc is a key downstream mediator of insulin action. Finally, we will validate our animal models by studying the correlation between IR phosphorylation and vimentin and c-myc expression in human HER2 overexpressing and triple negative breast cancers. At the conclusion of these studies, we anticipate that we will define many of the mechanisms involved in the effect of hyperinsulinemia on breast cancer progression and metastases. These results will be critical for the development of more appropriate interventions to treat breast (and other) cancers in the increasing number of women with obesity, T2D and the metabolic syndrome.
Obese women and those with Type 2 diabetes who develop breast cancer are more likely to have aggressive cancer, are less likely to respond to treatment and have a greater chance of dying. Through our studies we aim to determine the mechanisms through which high insulin levels and activation of the insulin receptor in tumors increase breast cancer aggression, and thus identify targets for new therapies that may be beneficial particularly in the increasing number of women with obesity and Type 2 Diabetes.
|Zelenko, Z; Gallagher, E J; Tobin-Hess, A et al. (2017) Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression. Oncogene 36:1394-1403|
|Shlomai, Gadi; Zelenko, Zara; Antoniou, Irini Markella et al. (2017) OP449 inhibits breast cancer growth without adverse metabolic effects. Endocr Relat Cancer 24:519-529|
|Mosa, Rasha; Huang, Lili; Wu, Yeda et al. (2017) Hexarelin, a Growth Hormone Secretagogue, Improves Lipid Metabolic Aberrations in Nonobese Insulin-Resistant Male MKR Mice. Endocrinology 158:3174-3187|
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|Zelenko, Zara; Gallagher, Emily Jane; Antoniou, Irini Markella et al. (2016) EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice. Endocr Relat Cancer 23:747-58|
|Shlomai, Gadi; Neel, Brian; LeRoith, Derek et al. (2016) Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy. J Clin Oncol 34:4261-4269|
|Gallagher, Emily J; LeRoith, Derek; Stasinopoulos, Marilyn et al. (2016) Polyol accumulation in muscle and liver in a mouse model of type 2 diabetes. J Diabetes Complications 30:999-1007|
|Gallagher, Emily J; LeRoith, Derek; Franco, Rebeca et al. (2016) Metabolic syndrome and pre-diabetes contribute to racial disparities in breast cancer outcomes: hypothesis and proposed pathways. Diabetes Metab Res Rev 32:745-753|
|Gallagher, Emily J; Zelenko, Zara; Tobin-Hess, Aviva et al. (2016) Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes. Diabetologia 59:2018-25|
|Gallagher, Emily Jane; LeRoith, Derek (2015) Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. Physiol Rev 95:727-48|
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