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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA128799-06A1
Application #
8694243
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2007-07-01
Project End
2019-05-31
Budget Start
2014-06-12
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$380,225
Indirect Cost
$155,225
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Zelenko, Z; Gallagher, E J; Tobin-Hess, A et al. (2016) Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression. Oncogene :
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
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
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
Rostoker, Ran; Ben-Shmuel, Sarit; Rashed, Rola et al. (2016) CD24 cell surface expression in Mvt1 mammary cancer cells serves as a biomarker for sensitivity to anti-IGF1R therapy. Breast Cancer Res 18:51
Hait, N C; Avni, D; Yamada, A et al. (2015) The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer. Oncogenesis 4:e156
Gallagher, Emily Jane; LeRoith, Derek (2015) Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. Physiol Rev 95:727-48
Ben-Shmuel, Sarit; Scheinman, Eyal J; Rashed, Rola et al. (2015) Ovariectomy is associated with metabolic impairments and enhanced mammary tumor growth in MKR mice. J Endocrinol 227:143-51
Rostoker, Ran; Jayaprakash, Anitha D; Sachidanandam, Ravi et al. (2015) Deep sequencing of mRNA in CD24(-) and CD24(+) mammary carcinoma Mvt1 cell line. Genom Data 5:399-401

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