The IGF Pathway as a Possible Link between Diabetes and Breast Cancer

The IGF system comprises a network of ligands (IGF-1 and IGF-2), which are highly
homologous to insulin; IGF-1 receptor (IGF-1R), which shares 55% homology with
the IR; and IGF-binding proteins (IGF-BPs) [16]. The IR and the IGF-IR are capable
of forming a hybrid receptor, which, like the IGF-IR, show high affinity to IGF-1 and
lower affinity to insulin. Activation of the IGF-IR by its ligand results in activation of the same proteins and pathways activated by the insulin and IR, i.e. the IRS, SHC adaptor proteins, PI3K and MAPK. Thus, the specificity of the IGF pathway depends mainly on the ligand and its receptor, and not on the downstream parts of the cascade.
The IGF system is considered to be a key regulatory pathway in breast cancer
and is an attractive target for the development of novel breast cancer therapies. High circulating levels of IGF-1 and IGF-BP3 are associated with increased risk of premenopausal breast cancer, and increased IGF-1 is considered to be a link between
obesity to increased risk of breast cancer [17]. However, type 2 diabetes usually affects postmenopausal women and, controlled for obesity, blood concentrations of IGF-1,IGF-2, and their binding proteins are usually not raised and may actually be reduced in both type 2 diabetes mellitus and the metabolic syndrome [18]. These findings suggest that the IGFs and the IGF-BPs may not play a major role in the association between diabetes and breast cancer. A high concentration of insulin could stimulate the IGF pathway in type 2 diabetes through the non-specific activation of the IGF-1R and the IGF-1R/IR hybrid receptor. However, the importance of this mechanism in the pathogenesis of breast cancer remains to be defined.