title: Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes.
abstract: Epidemiologic studies suggest that type 2 diabetes (T2D) increases breast cancer risk and mortality, but there is limited experimental evidence supporting this association. Moreover, there has not been any definition of a pathophysiological pathway that diabetes may use to promote tumorigenesis. In the present study, we used the MKR mouse model of T2D to investigate molecular mechanisms that link T2D to breast cancer development and progression. MKR mice harbor a transgene encoding a dominant-negative, kinase-dead human insulin-like growth factor-I receptor (IGF-IR) that is expressed exclusively in skeletal muscle, where it acts to inactivate endogenous insulin receptor (IR) and IGF-IR. Although lean female MKR mice are insulin resistant and glucose intolerant, displaying accelerated mammary gland development and enhanced phosphorylation of IR/IGF-IR and Akt in mammary tissue, in the context of three different mouse models of breast cancer, these metabolic abnormalities were found to accelerate the development of hyperplastic precancerous lesions. Normal or malignant mammary tissue isolated from these mice exhibited increased phosphorylation of IR/IGF-IR and Akt, whereas extracellular signal-regulated kinase 1/2 phosphorylation was largely unaffected. Tumor-promoting effects of T2D in the models were reversed by pharmacological blockade of IR/IGF-IR signaling by the small-molecule tyrosine kinase inhibitor BMS-536924. Our findings offer compelling experimental evidence that T2D accelerates mammary gland development and carcinogenesis,and that the IR and/or the IGF-IR are major mediators of these effects.
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: Ruslan
authors.initials: R
authors.lastname: Novosyadlyy
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Lann
authors.forename: Archana
authors.initials: A
authors.lastname: Vijayakumar
authors.forename: Anne
authors.initials: A
authors.lastname: Rowzee
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lazzarino
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fierz
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Pennisi
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.forename: Naamit
authors.initials: N
authors.lastname: Kurshan
authors.forename: Wilson
authors.initials: W
authors.lastname: Mejia
authors.forename: Stefania
authors.initials: S
authors.lastname: Santopietro
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006946:Hyperinsulinism / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000097:blood; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011728:Pyridones / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C504983:BMS 536924; D001562:Benzimidazoles; D007328:Insulin; D011728:Pyridones; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt