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Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression
Yvonne Fierz1, Ruslan Novosyadlyy, Archana Vijayakumar
1Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
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 nonobese, hyperinsulinemic mouse model of type 2 diabetes. MKR(+/+) mice were either crossed with mice expressing the polyoma virus middle T 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 beta3-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 insulin and IGF-I receptors in transformed mammary tissue.
Conclusions:
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.
Insights
Reducing high insulin levels through medication can slow breast cancer progression in type 2 diabetes models. This suggests early insulin-sensitizing therapy may lower breast cancer risk for diabetic patients.
Area of Science:
- Endocrinology
- Oncology
- Metabolic Syndrome
Background:
- Type 2 diabetes is linked to increased breast cancer risk and mortality.
- Hyperinsulinemia is a key factor connecting type 2 diabetes and breast cancer.
Purpose of the Study:
- To investigate if reducing insulin levels pharmacologically can slow breast cancer progression in type 2 diabetes.
Main Methods:
- Studied mammary tumor development in a hyperinsulinemic mouse model of type 2 diabetes (MKR(+/+) mice).
- Utilized genetically engineered mice and orthotopic tumor cell inoculation.
- Treated mice with a beta3-adrenergic receptor agonist (CL-316243) to improve insulin sensitivity.
Main Results:
- CL-316243 treatment lowered insulin levels in diabetic mice.
- Mammary tumor progression was attenuated across three different tumor models.
- Reduced phosphorylation of insulin and IGF-I receptors was observed in tumor tissue.
Conclusions:
- Insulin-sensitizing treatment effectively halts type 2 diabetes-driven mammary tumor growth.
- Early intervention with insulin-sensitizing therapies may decrease breast cancer risk and mortality in type 2 diabetes patients.
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