title: Mammalian target of rapamycin inhibition abrogates insulin-mediated mammary tumor progression in type 2 diabetes.
abstract: Type 2 diabetes increases breast cancer risk and mortality, and hyperinsulinemia is a major mediator of this effect. The mammalian target of rapamycin (mTOR) is activated by insulin and is a key regulator of mammary tumor progression. Pharmacological mTOR inhibition suppresses tumor growth in numerous mammary tumor models in the non-diabetic setting. However, the role of the mTOR pathway in type 2 diabetes-induced tumor growth remains elusive. Herein, we investigated whether the mTOR pathway is implicated in insulin-induced mammary tumor progression in a transgenic mouse model of type 2 diabetes (MKR mice) and evaluated the impact of mTOR inhibition on the diabetic state. Mammary tumor progression was studied in the double transgenic MMTV-Polyoma Virus middle T antigen (PyVmT)/MKR mice and by orthotopic inoculation of PyVmT- and Neu/ErbB2-driven mammary tumor cells (Met-1 and MCNeuA cells respectively). mTOR inhibition by rapamycin markedly suppressed tumor growth in both wild-type and MKR mice. In diabetic animals, however, the promoting action of insulin on tumor growth was completely blunted by rapamycin, despite a worsening of the carbohydrate and lipid metabolism. Taken together, pharmacological mTOR blockade is sufficient to abrogate mammary tumor progression in the setting of hyperinsulinemia, and thus mTOR inhibitors may be an attractive therapeutic modality for breast cancer patients with type 2 diabetes. Careful monitoring of the metabolic state, however, is important as dose adaptations of glucose- and/or lipid-lowering therapy might be necessary.
authors.affiliation: Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fierz
authors.forename: Ruslan
authors.initials: R
authors.lastname: Novosyadlyy
authors.forename: Archana
authors.initials: A
authors.lastname: Vijayakumar
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004435:Eating / Q000502:physiology; D005260:Female; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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