Sabtu, 31 Januari 2009

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 theinsulin-like growth factor (IGF)-1 pathway, altered regulation of endogenous sex hormones,altered regulation of adipocytokines.The Insulin Pathway and Breast CancerInsulin is a polypeptide hormone secreted from pancreatic -cells in response to elevationin glucose levels [7]. The first step in activation of the insulin pathway is bindingof insulin to the insulin receptor (IR). The primary targets for insulin are skeletalmuscle, adipose tissue and the liver, however many other tissues, including normalbreast tissue and breast cancer, express the IR. The IR is a tyrosine kinase receptor,composed of two extracellular -subunits and two transmembrane -subunits. Insulinbinding leads to autophosphorylation of tyrosine residues in the intracellular subunitsand thus activates the tyrosine kinase. Once activated, the IR phosphorylates a numberof 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 phosphatidylinositol3-kinase (PI3K), which turns on the Akt pathway. Binding of Shc tothe IR leads to activation of the extracellular signal-regulated kinase (ERK) cascade,one of the mitogen-activating protein kinase (MAPK) pathways [8]. Although themajor 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 in 159 breast cancer specimens and found it to be sixfold higher than in 33 samples of normal breast tissues, and also higher than in other normal tissues, including the liver. High IR content correlated positively with tumor size, grade and ER content. Mathieu et al. [13] found detectable IR levels in 444 of 584 (76%) breast cancer specimens and found it to be a strong predictor of disease-free survival. Similarly, analysis of IR expression in a cohort of 191 early breast cancer patients revealed an association between high IR expression and favorable prognostic factors and improved diseasefree
and overall survival [14].

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