IGFBP-3 can either inhibit or enhance EGF-mediated growth of breast epithelial cells dependent upon the presence of fibronectin.
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 [Tyr(1068)], 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.
McIntosh
Jamie
J
School of Clinical Sciences, IGFs and Metabolic Endocrinology Group, Learning and Research Building, 2nd Floor, University of Bristol, Southmead Hospital, Bristol BS10 5NB, United Kingdom.
Dennison
Godwin
G
Holly
Jeff M P
JM
Jarrett
Caroline
C
Frankow
Alexandra
A
Foulstone
Emily J
EJ
Winters
Zoe E
ZE
Perks
Claire M
CM
D019921:Biotinylation; D001940:Breast / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005353:Fibronectins / Q000737:chemistry*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology; D011863:Radioimmunoassay; D054460:rho-Associated Kinases / Q000378:metabolism
D005353:Fibronectins; D018972:Insulin-Like Growth Factor Binding Protein 3; D007797:Laminin; D011799:Quinazolines; D004815:Epidermal Growth Factor; D054460:rho-Associated Kinases; D000077156:Gefitinib