Alterations in both heparan sulfate proteoglycans and mitogenic activity of fibroblast growth factor-2 are triggered by inhibitors of proliferation in normal and breast cancer epithelial cells

Heparan sulfate proteoglycans (HSPG) are involved in the regulation of cellular proliferation, differentiation, and migration. We have studied the effect of three inhibitors of proliferation on S-35 incorporation into HSPG of the breast cancer cell lines MCF-7 and MDA-MB-231 and the normal breast epithelial cells (NBEC), Transforming growth factor beta-1 (TGF beta-1), which inhibits the proliferation of NBEC, but not of MCF-7 and MDA-MB-231, cells induced an increase in 35S incorporation of HSPG in NBEC, but had no effect on cancer cells. Sodium butyrate (NaB), which inhibits NBEC as well as cancer cell proliferation, induced an increase in S-35 incorporation into HSPG in all cell types studied. In contrast, retinoic acid had no effect on HSPG of breast epithelial cells. Modification of HSPG induced by TGF beta-1 or NaB treatments in normal and breast cancer epithelial cells resulted in an increase in I-125-fibroblast growth factor-2 (FGF-2) binding on HSPG, More importantly, NaB pretreatment resulted in an inhibition of the MCF-7 cell responsiveness to FGF-2, even though these cells remained sensitive to growth stimulation induced by serum or epidermal growth factor. These results indicate that changes in HSPG production are a key process involved in the mechanism of breast epithelial cell growth regulation. (C) 1998 Academic Press.