Diabetes Mellitus and Breast Cancer Possible Associating Mechanisms

Four major mechanisms may contribute to the association between type 2 diabetes mellitus and breast cancer (fig. 2): activation of the insulin pathway, activation of the insulin-like growth factor (IGF)-1 pathway, altered regulation of endogenous sex hormones, altered regulation of adipocytokines.

The Insulin Pathway and Breast Cancer

Insulin is a polypeptide hormone secreted from pancreatic p-cells in response to elevation in glucose levels [7]. The first step in activation of the insulin pathway is binding of insulin to the insulin receptor (IR). The primary targets for insulin are skeletal muscle, adipose tissue and the liver, however many other tissues, including normal breast tissue and breast cancer, express the IR. The IR is a tyrosine kinase receptor, composed of two extracellular a-subunits and two transmembrane p-subunits. Insulin binding leads to autophosphorylation of tyrosine residues in the intracellular subunits and thus activates the tyrosine kinase. Once activated, the IR phosphorylates a number of intracellular proteins, including members of the insulin receptor substrate family (IRS) and SHC adaptor protein. Binding of IRS to the IR leads to activation the phos-phatidylinositol 3-kinase (PI3K), which turns on the Akt pathway. Binding of Shc to the IR leads to activation of the extracellular signal-regulated kinase (ERK) cascade, one of the mitogen-activating protein kinase (MAPK) pathways [8]. Although the major role of insulin is metabolic, both the Akt and the MAPK pathways also have important roles in tumorigenesis. Indeed, insulin was found to stimulate cell cycle progression in MCF-7 breast cancer cells either by itself or synergistically with estradiol [9]. IRS-1 may also interact directly and activate the estrogen receptor (ER). Thus, activation of the insulin pathway may also affect the ER pathway [10].

The IR has a major role in the activation of the insulin pathway in breast cancer. The IR is expressed and can be stimulated by insulin in breast cancer cell lines, and overexpression of it can induce malignant transformation in breast epithelial cell lines. Stimulation by progestins, inactivation of p53 or activity of oncogenes such as Wnt-1, Neu and Ret can lead to overexpression of the IR in breast cancer [11].

Several clinical studies have investigated the role of the insulin pathway, and mainly the part played by the IR, in breast cancer. Papa et al. [12] measured IR content

Altered adipocytokine levels

Activation of the insulin/IGF-1 pathways

Reduced plasma adiponectin levels

Reduced plasma adiponectin levels

High IR expression in breast cancer Increased plasma insulin levels Insulin resistance

Inhibition of the AMPK pathway

Activation of the insulin/IGF-1 pathway

Activation of the insulin/IGF-1 pathway

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