Insulin-Mediated Acceleration of Breast Cancer Development and Progression in a Nonobese Model of Type 2 Diabetes

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.Fil: Novosyadlyy, Ruslan. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Lann, Danielle E.. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Vijayakumar, Archana. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Rowzee, Anne. Rutgers University; Estados UnidosFil: Lazzarino, Deborah A.. Rutgers University; Estados UnidosFil: Fierz, Yvonne. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Carboni, Joan M.. Bristol Myers Squibb Research Institute; Estados UnidosFil: Gottardis, Marco M.. Bristol Myers Squibb Research Institute; Estados UnidosFil: Pennisi, Patricia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; ArgentinaFil: Molinolo, Alfredo A.. National Institute of Dental and Craniofacial Research; Estados UnidosFil: Kurshan, Naamit. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Mejia, Wilson. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Santopietro, Stefania. No especifíca;Fil: Yakar, Shoshana. Icahn School of Medicine at Mount Sinai; Estados UnidosFil: Wood, Teresa L.. Rutgers University; Estados UnidosFil: LeRoith, Derek. Icahn School of Medicine at Mount Sinai; Estados Unido