Multifunctional roles of insulin-like growth factor binding protein 5 in breast cancer

Abstract

The insulin-like growth factor axis, which has been shown to protect cells from apoptosis, plays an essential role in normal cell physiology and in cancer development. The family of insulin-like growth factor binding proteins (IGFBPs) has been shown to have a diverse spectrum of functions in cell growth, death, motility, and tissue remodeling. Among the six IGFBP family members, IGFBP-5 has recently been shown to play an important role in the biology of breast cancer, especially in breast cancer metastasis; however, the exact mechanisms of action remain obscure and sometimes paradoxical. An in-depth understanding of IGFBP-5 would shed light on its potential role as a target for breast cancer therapeutics. IntroductionThere are six well-characterized insulin-like growth factor binding proteins (IGFBP-1 to IGFBP-6) isolated and characterized from a variety of vertebrate species, including humans; the IGFBPs range in size from 216 to 289 amino acids, with molecular masses between 24 and 44 kDa [1,2]. These IGFBPs share a highly conserved protein domain structure consisting of three main parts (N, L, and C domains). The N and C domains contain insulin-like growth factor (IGF)-binding sites, and the L domain carries proteolytic degradation sites. Some other putative IGFbinding proteins with less sequence homology have been found, but they have not been well studied [3]. Numerous studies, however, have found that IGFBPs also function independently of the IGF signaling pathway. IGFBPs may interact with proteins other than IGFs, may be cleaved, may bind to their own receptor on the membrane, and may locate both extracellularly and intracellularly [11]. Importantly, there is increasing evidence that IGFBP-2, IGFBP-3, and IGFBP-5 are important players in the phenotypes of various cancers [2,12,13]. Pertinent to the present review, IGFBP-5 has been associated with breast metastasis [9,14].In the present article, we review literature reports on the functions and regulation of IGFBP-5, and particularly their potential role in breast cancer development and progression. IGFBP-5 gene and protein

Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma

“…In our study, we find that IGFBP5 suppresses metastatic phenotypes in OS. These findings are supported by the reported functions of the three conserved domains of this protein, the N-terminal, C-terminal and L domains (Schneider et al, 2002;Akkiprik et al, 2008). In particular, the C-terminal domain might be involved in the inhibition of OS migration, invasion and metastasis.…”

“…Additionally, IGFBP5 is downregulated in renal and cervical tumors, but appears to be upregulated in high-grade ovarian carcinoma and thyroid papillary carcinoma (Stolf et al, 2003;Cheung et al, 2005;Takahashi et al, 2005;Wang et al, 2006). These conflicting results may be due to IGFBP5 mediating its effects in both IGF-dependent and IGF-independent pathways (Akkiprik et al, 2008). In our study, we find that IGFBP5 suppresses metastatic phenotypes in OS.…”

“…In particular, the C-terminal domain might be involved in the inhibition of OS migration, invasion and metastasis. This domain has been shown to interact with extracellular matrix proteins, such as fibronectin, thrombospondin-1, osteopontin and vitronectin (Akkiprik et al, 2008). In addition, IGFBP5 contains a total of three heparin-binding motifs in the C-terminal and L domains (Song et al, 2001).…”

“…The N-terminal domain of IGFBP5 has been shown to bind to IGF, thereby regulating mitogenic activity (Akkiprik et al, 2008). Binding of IGFBP5 to IGF is believed to prevent or modulate IGF binding to the IGF receptor (Akkiprik et al, 2008).…”

“…The N-terminal domain of IGFBP5 has been shown to bind to IGF, thereby regulating mitogenic activity (Akkiprik et al, 2008). Binding of IGFBP5 to IGF is believed to prevent or modulate IGF binding to the IGF receptor (Akkiprik et al, 2008). Additionally, the C-terminal domain of IGFBP5 contains a nuclear localization signal and might mediate the observed (Schneider et al, 2001;Akkiprik et al, 2008).…”