Antiproliferative actions of insulin-like growth factor binding protein (IGFBP)-3 in human breast cancer cells.
A number of lines of evidence suggest that IGFs are important mitogens in human breast cancer: (1) IGFs are the most potent growth factor in human breast cancer cells; (2) estrogen stimulates expression of IGF-II and the type 1 IGF receptor; and (3) stromal cells express IGFs, which may act in a paracrine manner. Numerous studies have demonstrated that IGFBPs modulate the mitogenic effects of IGFs in the local environment. In particular, we have recently demonstrated that IGFBP-3 inhibits the growth of Hs578T and MDA-MB-231 human breast cancer cells in an IGF-independent manner. Further studies revealed the existence of cell surface-associated IGFBP-3 receptors. Receptor binding and the subsequent antiproliferative action of IGFBP-3 was inhibited by IGFs, owing to the formation of an IGF-IGFBP-3 complex that prevents the binding of IGFBP-3 to its receptors. In addition, exogeneously added soluble heparin or heparan sulfate inhibited the binding of IGFBP-3 to the cell surface in a dose-dependent manner. However, when heparin and heparan sulfate linkages of glycosaminoglycans on the cell surface were enzymatically remove, IGFBP-3 binding was only minimally affected. These data suggest that soluble heparin or heparan sulfate forms a complex with IGFBP-3, thereby inhibiting receptor binding of IGFBP-3, rather than competing with cell-surface glycosaminoglycans for binding of IGFBP-3. Additionally, the role of IGFBP-3 in the antiproliferative effects of transforming growth factor (TGF)-beta and retinoic acid (RA) is supported by our observations that: (1) inhibition of IGFBP-3 gene expression using an IGFNBP-3 antisense oligodeoxynucleotide not only blocks TGF-beta and RA simulation of IGFBP-3 production by up to 90%m but also inhibits their antiproliferative effects by 40-60%; and (2) treatment with IGF-II and IGF-II analogs diminish TGF-beta effects by blocking TGF-beta induced binding of IGFBP-3 to the cell surface. Taken together, our results support the hypothesis that IGFBP-3 is an important antiproliferative factor in human breast cancer, acting in an IGF-independent manner in addition to its ability to modulate the binding of IGF peptides to IGF receptors.
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Department of Pediatrics, School of Medicine, Oregon Health Sciences University, Portland 97201-3042, USA.
Gucev
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Müller
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Rosenfeld
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D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000494:pharmacology*; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018972:Insulin-Like Growth Factor Binding Protein 3; D016376:Oligonucleotides, Antisense; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D010450:Endopeptidases; C080473:insulin-like growth factor binding protein-3 protease