Tyrosine kinase signalling in breast cancer: Insulin-like growth factors and their receptors in breast cancer

The IGF system is composed of IGF ligands, receptors, and binding proteins. These system components form a highly regulated network of interactions both among themselves and between other biologic signaling pathways.The two well-characterized ligands, IGF-1 and IGF-II, are mitogenic peptides that are highly homologous to each other and to insulin [1]. Whereas insulin is composed of two chains (A and B) of 21 and 30 amino acids, respectively, the IGFs are single-chain molecules that retain the equivalent of the connecting (C)-peptide of proinsulin between the A and B domains. IGF-1 and IGF-II are thought to have autocrine, endocrine, and paracrine roles in normal mammary development and in the etiology of breast cancer [2,3,4,5].Unlike insulin, circulating IGFs are found complexed to high-affinity binding proteins known as IGF-binding proteins (IGFBPs). Six distinct species have been cloned. An additional family of structurally homologous proteins has been identified and named IGFBP-related proteins, because their affinity for the IGFs is significantly lower than that of the IGFBPs [6,7]. Cleavage of IGFBPs by specific proteases modulates levels of free IGFs and IGFBPs, and thereby their actions. In addition, IGFBPs may also have effects that are completely independent of their role in modulating the action of IGF [8].The cellular actions of IGFs are mediated by type I and type II receptors, insulin receptor, and insulin receptor-IGF1R hybrids. The type II IGF receptor (IGF2R) is a multifunctional nontyrosine kinase receptor [9,10,11] that is also known as the cation-independent mannose-6-phosphate receptor, and its function in regulating the action of IGF-II has been controversial. IGF1R is a glycosylated heterotetramer that is composed of two extracellular α-subunits and two transmembrane β-subunits that have intrinsic tyrosine kinase activity [12,13]. This review focuses on IGF1R-mediated signaling and its relevance in breast cancer.Activation of the IGF1R by IGFs