Insulin Receptor Loss Impairs Mammary Tumorigenesis in Mice

Summary Breast cancer (BC) prognosis and outcome are adversely affected by obesity. Hyperinsulinemia, common in obese state, is associated with higher risk of death and recurrence in BC. Up to 80% of breast cancers overexpress the insulin receptor (INSR), which correlates with worse prognosis. INSR role in mammary tumorigenesis was tested by generating MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of INSR . In both models, deletion of either one or both copies of INSR led to a marked delay in tumor onset and burden. Longitudinal phenotypic characterization of mouse tumours and cells revealed that INSR deletion impacted tumour initiation, not progression and metastasis. INSR upheld a bioenergetic phenotype in non-transformed mammary epithelial cells, independent of its kinase activity. Similarity of phenotypes elicited by deletion of one or both copies of INSR suggest a dose-dependent threshold for INSR impact on mammary tumorigenesis.