Insulin-Like-Growth Factor-Binding-Protein 7: An Antagonist to Breast Cancer

Abstract

1.1 The insulin-like growth factor (IGF) system The insulin-like growth factor (IGF) system has been shown to have an integral role in normal growth and development, and in the pathophysiology of various cancers. The IGF system is comprised of a series of circulating ligands (IGF-1, IGF-2), transmembrane receptor tyrosine kinases (IGF-1R, IGF-2R, and the insulin receptor (IR), high affinity ligandbinding proteins (IGFBP1-6), IGFBP proteases, and several low affinity IGFBP-related proteins (IGFBP-rp1 to 10) that work in unison to regulate cell growth [1]. There are two key circulating ligands, IGF-1 and IGF-2, which share approximately 50% structural homology with insulin[2]. IGF-1 is produced primarily in the liver in response to circulating levels of growth hormone(GH) [3]. IGF-1 and IGF-2 are highly homologous small peptide hormones of approximately 7 kDa molecular mass, which are important mitogens that affect cell growth and metabolism [2]. IGFs interact with specific cell surface receptors, designated type I and type 2 IGF receptors, and can also interact with insulin receptor (IR). The type I IGF receptor (IGF-1R) is a transmembrane heterotetramer consisting of 2 extracellular alpha subunits and two intracellular beta subunits linked by disulfide bonds (fig 1). The intracellular component of IGF-1R has intrinsic tyrosine kinase activity that requires ligand binding for activation [4]. The IGF-1R and the IR share approximately 60% homology which allows them to form hybrid receptors [5]. As a result of this homology, IGF-1R can be activated not only by IGF-1 but also IGF-2 and insulin, although the affinity of IGF-1R for IGF-2 and insulin is approximately 10 fold and 1000 fold lower than for IGF-1, respectively [6]. The type 2 IGF receptor (IGF-2R), which is identical to the cationindependent mannose-6-phosphate receptor, binds IGF-2 with 500 fold increased affinity over IGF-1[7]. IGF-2R does not bind insulin. Most of the biological activity of IGF-2 is thought to be mediated through binding IGF-1R[7]. IGF-2 is known to function primarily as a scavenger receptor, regulating circulating IGF-II levels through internalization and degradation [7].