Acceleration of breast cancer development and progression in a non-obese model of type 2 diabetes is reversed by antidiabetic treatment and blockade of insulin and IGF-I receptors

RUSLAN NOVOSYADLYY; YVONNE FIERZ; DANIELLE E. LANN; ARCHANA VIJAYAKUMAR; ANNE ROWZEE; DEBORAH A. LAZZARINO; PATRICIA A. PENNISI; ALFREDO A. MOLINOLO; NAAMIT KURSHAN; WILSON MEJIA; STEFANIA SANTOPIETRO; SHOSHANA YAKAR; TERESA L. WOOD; DEREK LEROITH

New Orleans, Louisinana USA

Congreso; 69th Scientific Sessions , American Diabetes Association Annual Meeting; 2009

American Diabetes Association

Numerous epidemiological studies suggest that type 2 diabetes (T2D) significantly increases breast cancer risk and mortality. However, there is limited experimental evidence of this association. Moreover, a major pathophysiological mechanism underlying the tumor-promoting activity of diabetes remains unidentified. In the present study, the molecular mechanisms that link T2D and breast cancer development and progression were studied. To study this association, the transgenic MKR mouse model of T2D was employed. In MKR mice, the transgene encoding human insulin-like growth factor I (IGF-I) receptor has a point mutation (K1003 substituted by R1003) and is driven by the muscle creatine kinase promoter, resulting in inactivation of insulin and IGF-I receptors (IR and IGF-IR) exclusively in skeletal muscle. MKR females are non-obese, yet they are hyperinsulinemic, insulin resistant and glucose intolerant. Female MKR mice demonstrate accelerated mammary gland development and an increased number of insulin receptors, enhanced phosphorylation of IR/IGF-IR and hyperactivation of the PI3K/Akt pathway in mammary tissue. The metabolic abnormalities of MKR mice promote a more aggressive tumor phenotype and enhanced tumor growth in transgenic PyVmT (polyoma virus middle T antigen) and Neu/ErbB2 models, syngeneic Met-1 and MCNeuA orthograft models and in the model of 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenesis. Breast tumor tissue extracted from diabetic mice reveals markedly increased phosphorylation of the IR/IGF-IR and Akt, whereas ERK1/2 phosphorylation remains largely unaffected. Pharmacological means that correct hyperinsulinemia (beta-3-adrenergic receptor agonist CL-316243) or block the IR/IGF-IR (dual tyrosine kinase inhibitor BMS-536924) reverse the tumor-promoting effects of diabetes. Taken together, our data provide compelling evidence that (i) hyperinsulinemia accelerates mammary gland development and mammary carcinogenesis, and (ii) the IR and the IGF-IR are the major mediators of this effect.