Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells.
The human breast cancer cell lines MCF-7 and MDA-MB-231 differ in their responsiveness to fibroblast growth factor-2 (FGF-2). This growth factor stimulates proliferation in well-differentiated MCF-7 cells, whereas the less well-differentiated MDA-MB-231 cells are insensitive to this molecule. To investigate the potential regulation of FGF-2 mitogenic activity by heparan sulfate proteoglycans (HSPG), we have treated human breast cancer cells by glycosaminoglycan degrading enzymes or a metabolic inhibitor of proteoglycan sulfation: sodium chlorate. The interaction between FGF-2 and proteoglycans was assayed by examining the binding of 125I-FGF-2 to breast cancer cell cultures as well as to cationic membranes loaded with HSPG. Using MCF-7 cells, we showed that heparinase treatment inhibited FGF-2 binding to HSPG and completely abolished FGF-2 induced growth; chlorate treatment of MCF-7 cells decreased FGF-2 binding to HSPG and cell responsiveness in a dose-dependent manner. This demonstrates a requirement of adequately sulfated HSPG for FGF-2 growth-promoting activity on MCF-7 cells. In highly invasive MDA-MB-231 cells which produce twice as much HSPG as MCF-7 cells and which are not normally responsive to exogenously added FGF-2, chlorate treatment decreased FGF-2 binding to HSPG and induced FGF-2 mitogenic effect. This chlorate effect was dose dependent and observed at concentrations of 10-30 mM; higher chlorate concentrations completely abolished the FGF-2 effect. This shows that the HSPG level of sulfation can also negatively regulate the biological activity of FGF-2. Taken together, these results demonstrate a crucial role for HSPG in both positive and negative control of FGF-2 mitogenic activity in breast cancer cell proliferation.
Delehedde
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Unité de Dynamique des Cellules Embryonnaires et Cancéreuses, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq Cedex, 59655, France. Hubert.Hondermarck@univ-lille1.fr
Deudon
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Boilly
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Hondermarck
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D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D002704:Chlorates / Q000494:pharmacology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008934:Mitogens / Q000494:pharmacology; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism*; D013431:Sulfates / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002704:Chlorates; D016222:Fibroblast Growth Factor 2; D019812:Heparan Sulfate Proteoglycans; D019763:Heparin Lyase; D006497:Heparan Sulfate; D008934:Mitogens; D011133:Polysaccharide-Lyases; D011509:Proteoglycans; D013431:Sulfates