Insulin-like growth factor binding protein-1 (IGFBP-1) targets both the insulin-like growth factor (IGF) and integrin pathways for the inhibition of breast cancer cell motility.

Abstract #402

The insulin-like growth factor (IGF) system is a relevant therapeutic target for the treatment of breast cancer. Besides receptor targeted therapies, inhibition of ligand-receptor interactions by IGF-sequestering agents such as IGF binding proteins has also proven efficacious. We have used IGF binding protein (IGFBP-1) to neutralize IGF action. This binding protein both binds IGF-I and binds integrins through a RGD sequence and blocks IGF-I induced proliferation and motility. To examine the functional motifs in IGFBP-1, we studied breast cancer cells and examined IGF-induced signaling and biology after exposure to native recombinant human IGFBP-1 (rhIGFBP-1), reduced rhIGFBP-1, and an RGD mutant (Trp-Gly-Asp, WGD) rhIGFBP-1. Native and WGD IGFBP-1 retained IGF-I binding affinity, whereas reduced IGFBP-1 lost ligand binding as confirmed by western ligand blot. Chronic (>3 hour) 80nM rhIGFBP-1 treatment abrogated paxillin phosphorylation and initiated MAPK activation in an IGF-independent manner, and inhibited basal motility and adhesion to fibronectin. While 80nM native rhIGFBP-1 abolished IGF-induced IRS, PKB/Akt and ERK phosphorylation, 80nM reduced rhIGFBP-1 only inhibited IGF-induced PKB/Akt phosphorylation. rhIGFBP-1 inhibited IGF-induced motility, adhesion to fibronectin and anchorage independent growth at IC50 40-80nM. In contrast, efficacy of reduced IGFBP-1 ranged between 80-160nM. Both the IGF-binding and the integrin-binding mechanisms of action of IGFBP-1 were inhibitory to IGF-induced integrin functions. In contrast, IGF-neutralization (but not integrin effects) was required for the inhibition of biology of breast cancer cells in monolayer. Therefore, this study demonstrates that IGFBP-1 has two distinct functional motifs that contribute to the inhibition of breast cancer basal and IGF-induced functions, and that the integrin and IGF-binding motifs of IGFBP-1 cooperatively inhibit IGF-action.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 402.