The proliferative and migratory activities of breast cancer cells can be differentially regulated by heparan sulfates

To explore how heparan sulfate (HS) controls the responsiveness of the brea st cancer cell lines MCF-7 and MDA-MB-231 to fibroblast growth factors (FGF s), we have exposed them to HS preparations known to have specificity for F GF-1 (HS glycosaminoglycan (HSGAG A)) or FGF-2 (HSGAGB). Proliferation assa ys confirmed that MCF-7 cells were highly responsive to FGF-2 complexed wit h GAGB, whereas migration assays indicated that FGF-1/HSGAGA combinations w ere stimulatory for the highly invasive MDA-MB-231 cells. Quantitative poly merase chain reaction for the levels of FGF receptor (PGFR) isoforms reveal ed that MCF-7 cells have greater levels of FGFR1 and that MDA-MB-231 cells have greater relative levels of FGFR2. Cross-linking demonstrated that FGF- 2/HSGAGB primarily activated FGFR1, which in turn up regulated the activity of mitogen-activated protein kinase; in contrast, FGF-1/HSGAGA led to the phosphorylation of equal proportions of both FGFR1 and FGFR2, which in turn led to the up-regulation of Src and p125(FAK). MDA-MB-231 cells were parti cularly responsive to vitronectin substrates in the presence of FGF-1/HSGAG A, and blocking antibodies established that they used the alpha(v)beta(3) i ntegrin to bind to it. These results suggest that the clustering of particu lar FGFR configurations on breast cancer cells induced by different HS chai ns leads to distinct phenotypic behaviors.