Dysregulation of heparan-sulfate proteoglycan (HSPG) biosynthetic enzymes plays a critical role at various stages of tumorigenesis and we have recently shown that, in the chondrosarcoma cell line H-HEMC-SS, a number of HS sulfotransferase genes are subject to epigenetic silencing by DNA methylation (Bui et al., 2010).This was particularly noticeable with 3-OST3A, which was extensively hypermethylated, and reinstating the expression of this gene was accompanied by a significant reduction in proliferation and migration and an increase in adhesion capability of these cells.Were this to be a common phenomenon in tumour cells, it would point to a role for 3-OST3A as a tumor suppressor.One of the key methods by which HSPG controls cancer is by regulating interactions between cells and signalling molecules, primarily FGFs.FGFs are a family of heparin-binding growth factors, which influence cell growth and proliferation as well as survival via MAP-Kinase and AKT signaling pathway in cancer cells.In this study, we examined the mechanism of epigenetic regulation of 3-OST3A expression in the breast cancer cell lines MCF-7 and MDA-MB-231, and the influence that this enzyme has over the phenotype of these tumor cells.Our results provide a first evidence for specific epigenetic regulation of 3-OST3A gene resulting in altered HSPG sulfation and point to a defect of 3-O-sulfation as an important factor in breast cancer process.Whether 3-OST3A may act as a tumor suppressor gene and whether it regulates FGF-HS interactions in breast cancer cells is currently under investigation.