IGFBP-3 Can Either Inhibit or Enhance EGF-mediated Growth of Breast Epithelial Cells Dependent upon the Presence of Fibronectin

• Published in: The Journal of biological chemistry Vol. 285; no. 50; pp. 38788 - 38800
• Main Authors: McIntosh, Jamie, Dennison, Godwin, Holly, Jeff M.P., Jarrett, Caroline, Frankow, Alexandra, Foulstone, Emily J., Winters, Zoe E., Perks, Claire M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.12.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Biotinylation; Breast - metabolism; Breast Cancer; Breast Neoplasms - metabolism; Carcinogenesis; Cell Biology; Cell Growth; Cell Line, Tumor; Cell Surface; Cell Surface Receptor; Cellular Regulation; EGF; Epidermal Growth Factor - metabolism; Fibronectin; Fibronectins - chemistry; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; IGFBP-3; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Laminin - chemistry; MAP Kinase Signaling System; Phosphorylation; Quinazolines - pharmacology; Radioimmunoassay; rho-Associated Kinases - metabolism; Cell Surface; IGFBP-3; EGF; Cellular Regulation; Cell Growth; Cell Surface Receptor; Breast Cancer; Carcinogenesis; Fibronectin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.177311

Progression of breast cancer is associated with remodeling of the extracellular matrix, often involving a switch from estrogen dependence to a dependence on EGF receptor (EGFR)/HER-2 and is accompanied by increased expression of the main binding protein for insulin-like growth factors (IGFBP-3). We have examined the effects of IGFBP-3 on EGF responses of breast epithelial cells in the context of changes in the extracellular matrix. On plastic and laminin with MCF-10A normal breast epithelial cells, EGF and IGFBP-3 each increased cell growth and together produced a synergistic response, whereas with T47D breast cancer cells IGFBP-3 alone had no effect, but the ability of EGF to increase cell proliferation was markedly inhibited in the presence of IGFBP-3. In contrast on fibronectin with MCF-10A cells, IGFBP-3 alone inhibited cell growth and blocked EGF-induced proliferation. With the cancer cells, IGFBP-3 alone had no effect but enhanced the EGF-induced increase in cell growth. The insulin-like growth factor-independent effects of IGFBP-3 alone on cell proliferation were completely abrogated in the presence of an EGFR, tyrosine kinase inhibitor, Iressa. Although IGFBP-3 did not affect EGFR phosphorylation [Tyr1068], it was found to modulate receptor internalization and was associated with activation of Rho and subsequent changes in MAPK phosphorylation. The levels of fibronectin and IGFBP-3 within breast tumors may determine their dependence on EGFR and their response to therapies targeting this receptor.