Journal
DIABETES
Volume 59, Issue 3, Pages 686-693Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-1291
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- NCI NIH HHS [1R01CA128799-01A1, R01 CA128799] Funding Source: Medline
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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 beta(3)-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-1 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. Diabetes 59:686-693, 2010
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