Insulin Recepto Loss Impairs Mammary Tumourigenesis in Mice

Breast cancer (BC) prognosis and outcome are adversely affected by increased body weight, obesity, and the obesity-associated type 2 diabetes. Hyperinsulinemia, common in the obese state, has been 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. To directly probe the role of insulin signaling in mammary tumorigenesis, we generated the MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of the INSR. In both models, deletion of either one or both copies of the INSR in the mammary gland led to a marked delay in tumor onset and burden, including in mice fed to mimic conditions of human obesity. Phenotypic characterization and longitudinal monitoring of mouse tumours, and ex vivo analysis of mammary cells from the generated mouse models revealed that tumor initiation, rather than progression and metastasis, were impacted by INSR deletion. The similarity of phenotypes elicited by the deletion of one or both copies of INSR indicates that there is a dose-dependent threshold for the contribution of INSR to mammary tumorigenesis, with major implications for primary and secondary prevention of breast cancer in the obese.

Department dc:contributor.department

Medical Biophysics

Year dc:date.issued

2023

Author dc:creator

• Podmore, Lauren Michelle

Advisor dc:contributor.advisor

• Stambolic, Vuk

• bioenergetic fitness
• breast cancer
• insulin receptor
• mouse models
• obesity

Handle dc:identifier.uri

http://hdl.handle.net/1807/130119

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/130119