Figure 2: Model of how Heparan sulfate proteoglycans and heparanase participate in the epithelial-to-mesenchymal transition of a breast cancer cell. When a specific factor, such as TGF-β, stimulates its receptor on the tumor cell surface (1), the signaling cascade triggers transcriptional changes (2) that lead to a differential expression of specific receptors (3), which will allow the tumor cell to become responsive to other available factors that will culminate in the transition from an epithelial to a mesenchymal state (4). During this process, these transcriptional changes also lead to higher degree of sulfation of heparan sulfate chains (5), enhancing the cell ability to bind more extracellular molecules. Also, heparanase expression takes place (6), enhancing tumor angiogenesis (7) and degrading heparan sulfate chains (8) that will no longer be internalized, staying in the extracellular matrix bound with factors that also cooperate in the epithelial-to-mesenchymal transition process. Expression of extracellular matrix-degrading enzymes (9), such as metalloproteinases, promote extracellular matrix degradation (10) and heparan sulfate proteoglycans shedding (11). These processes altogether culminate in a complete transformation of an epithelial tumor cell into a mesenchymal phenotype (12) able to invade the neighboring tissue and circulation.