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The Her2oncogene is expressed in ∼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 Neu-NT(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 Neu-NTmammary tumor formation. In tumor tissues removed at 2, 4, and 6 weeks of Neu-NToverexpression, we observed increased tumor mass and higher phosphorylation of the insulin receptor/IGF1 receptor, 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 further increase in tumor weight was observed in MTB/TAN/MKR+/+compared with MTB/TAN mice, the number of lung metastases was significantly higher in MTB/TAN/MKR+/+mice compared with controls (MTB/TAN/MKR+/+16.41±4.18 vs MTB/TAN 5.36±2.72). In tumors at the 6-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. [ABSTRACT FROM AUTHOR]