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. Cancer Res; 70(2); 741-51. ©2010 AACR.

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

“…This observation is consistent with previous reports (Novosyadlyy et al, 2010reviewed in Pollak, 2008) that neoplasms can be growth-stimulated by insulin, and by our observation that MC38 cells are mitogenically responsive to physiological insulin concentrations in vitro. The increased insulin receptor activation associated with the high-fat diet was attenuated by metformin, consistent with the insulin-lowering effects of the drug.…”

“…As hyperinsulinemia can stimulate in vivo growth of certain neoplasms (Venkateswaran et al, 2007;Pollak, 2008;Novosyadlyy et al, 2010), the insulin-lowering action of metformin may contribute to its antineoplastic activity. Previous results (Algire et al, 2008) showed that metformin attenuated tumor growth in a murine model of type II diabetes, while having no effect on tumor growth in mice on a control diet, thus raising questions regarding the 'direct' AMPK-mediated antineoplastic effects of metformin vs the 'indirect' insulinlowering actions of metformin as the mechanism by which metformin attenuates tumor growth in in vivo models.…”

Diabetes, Overweight and Risk of Postmenopausal Breast Cancer: A Case-Control Study in Uruguay

“…Because the IGF-I system can be cross-activated by insulin, the synergic effects of IGF-I and estrogen may also play a role in the etiology of BC in the hyperinsulinemic state of type 2 diabetes (Chaudhuri et al, 1986, Guastamacchia et al, 2003. Recent experimental findings evidenced that Type 2 diabetes accelerates mammary gland development and carcinogenesis and that the insulin resistance and/or the IGF are major mediators of these effects (Novosyadlyy et al, 2010). If alterations of endogenous estrogen concentrations indeed play an important role in the association of type 2 diabetes with the risk of BC, this association is expected to be stronger for tumours that are estrogen receptor positive, which was confirmed in the Nurses Health Study (Michels et al, 2003).…”

Prognostic influence of metformin as first‐line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes

“…[1][2][3][4][5][6][7][8][9] Antidiabetic drugs also reportedly have different effects on cancer risk and prognosis. [10][11][12][13][14][15] For example, metformin, a biguanide derivative for the treatment of type 2 diabetes, has been associated with a reduced risk of cancer risk and mortality in diabetic patients; and insulin or insulin secretagogue use was associated with an increased risk of certain cancers, such as breast cancer, colorectal cancer, pancreatic cancer, bladder cancer, etc. [10][11][14][15][16] Although epidemiologic studies have indicated that metformin lowers the risk of several types of cancer in diabetic patients, [9][10][11]13,14,17 the underlying mechanisms remain unclear.…”