Document Detail

IGFBP-3 can either inhibit or enhance EGF-mediated growth of breast epithelial cells dependent upon the presence of fibronectin.
MedLine Citation:
PMID:  20851879     Owner:  NLM     Status:  MEDLINE    
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.
Jamie McIntosh; Godwin Dennison; Jeff M P Holly; Caroline Jarrett; Alexandra Frankow; Emily J Foulstone; Zoe E Winters; Claire M Perks
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-01-10     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38788-800     Citation Subset:  IM    
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.
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MeSH Terms
Breast / metabolism*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Epidermal Growth Factor / metabolism*
Fibronectins / chemistry*
Gene Expression Regulation, Neoplastic*
Insulin-Like Growth Factor Binding Protein 3 / metabolism*
Laminin / chemistry
MAP Kinase Signaling System
Quinazolines / pharmacology
rho-Associated Kinases / metabolism
Reg. No./Substance:
0/Fibronectins; 0/Insulin-Like Growth Factor Binding Protein 3; 0/Laminin; 0/Quinazolines; 62229-50-9/Epidermal Growth Factor; EC Kinases; S65743JHBS/gefitinib

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