Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression.
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.


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.
Fierz
Yvonne
Y
Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Novosyadlyy
Ruslan
R
Vijayakumar
Archana
A
Yakar
Shoshana
S
LeRoith
Derek
D
D000818:Animals; D001823:Body Composition / Q000187:drug effects; D045744:Cell Line, Tumor; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004435:Eating / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011120:Polyomavirus / Q000235:genetics; D012307:Risk Factors
D004149:Dioxoles; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate