Abstract

Objective: Type 2 diabetes increases breast cancer risk and mortality and hyperinsulinemia has been identified as a major factor linking these two diseases. Thus, we hypothesized that pharmacological reduction of elevated insulin levels would attenuate type 2 diabetes-mediated mammary tumor progression.

Research Design and Methods: We studied mammary tumor development in MKR^+/+ mice, a non-obese, hyperinsulinemic mouse model of type 2 diabetes. MKR^+/+ mice were either crossed with mice expressing the Polyoma Virus middle T (PyVmT) oncogene specifically in the mammary gland, or inoculated orthotopically with the mouse mammary tumor cell lines Met-1 and MCNeuA. MKR^+/+ or control mice harboring tumors were treated with CL-316243, a specific β₃-adrenergic receptor agonist, which sensitizes insulin action but has no direct effect on the mouse mammary epithelium or Met-1 and MCNeuA cells.

Results: CL-316243 treatment significantly reduced the elevated insulin levels in MKR^+/+ mice and, as a consequence, attenuated mammary tumor progression in the three tumor models tested. This effect was accompanied by reductions in phosphorylation of the insulin and IGF-I receptors in transformed mammary tissue.

Conclusion: Insulin sensitizing treatment is sufficient to abrogate type 2 diabetes-mediated mammary tumor progression. Therefore, early administration of insulin sensitizing therapy may reduce breast cancer risk and mortality in patients with type 2 diabetes.