TY - JOUR
T1 - Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression
AU - Fierz, Yvonne
AU - Novosyadlyy, Ruslan
AU - Vijayakumar, Archana
AU - Yakar, Shoshana
AU - LeRoith, Derek
PY - 2010/3
Y1 - 2010/3
N2 - 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 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 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.
AB - 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 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 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.
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U2 - 10.2337/db09-1291
DO - 10.2337/db09-1291
M3 - Article
C2 - 19959755
AN - SCOPUS:77950354885
SN - 0012-1797
VL - 59
SP - 686
EP - 693
JO - Diabetes
JF - Diabetes
IS - 3
ER -