Epidemiological studies suggest a positive association between obesity and type 2 diabetes mellitus (T2D) with the risk of cancer and cancer-related mortality. Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels of steroid and peptide hormones, and inflammatory markers appear to play a role in the connection between these different diseases. Medications, such as metformin and exogenous insulin, used to treat T2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin and IGF1 systems are being developed for use in cancer therapy.

The Her2 oncogene is expressed in approximately 25% of human breast cancers and is associated with metastatic progression and poor outcome. Epidemiological studies report that breast cancer incidence and mortality rates are higher in women with type 2 diabetes. Here we use a mouse model of Her2-mediated breast cancer on a background of hyperinsulinemia to determine how elevated circulating insulin levels affect Her2-mediated primary tumor growth and lung metastasis. Hyperinsulinemic (MKR+/+) mice were crossed with doxycycline-inducible NeuNT (MTB/TAN) mice to produce the MTB/TAN/MKR+/+ mouse model. Both MTB/TAN and MTB/TAN/MKR+/+ mice were administered doxycycline in drinking water to induce NeuNT mammary tumor formation. In tumor tissues removed at two, four and six weeks of Neu-NT overexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor (IR)/insulin-like growth factor receptor 1 (IGF-1R), suggesting that activation of these receptors in conditions of hyperinsulinemia could contribute to the increased growth of mammary tumors. After 12 weeks on doxycycline, although no significant further increase in tumor weight was observed in MTB/TAN/MKR+/+ compared to MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+ mice compared to controls (MTB/TAN/MKR+/+ 16.41 ± 4.18 vs. MTB/TAN 5.36 ± 2.72). In tumors at the six week time-point, we observed an increase in vimentin, a cytoskeletal protein and marker of mesenchymal cells, associated with epithelial-to-mesenchymal transition and cancer associated fibroblasts. We conclude that hyperinsulinemia in MTB/TAN/MKR+/+ mice resulted in larger primary tumors, with more mesenchymal cells and therefore, more aggressive tumors with more numerous pulmonary metastases.

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