The potential mechanisms that versican enhances breast cancer cell metastasize to bone. The interaction between breast cancer cells and tumor stroma induce tumor cells and stromal cells expressing enhanced cytokins TGF-β 1, TNF-α, and extracellular matrix – versican. Enhanced expression of versican promotes tumor cells expressing enhanced levels of pEGFR, pERK, and pAKT. Expression of ERK enhances tumor cell migration, invasion, growth, and metastasis. While expression of pAKT enhances tumor cell chemical resistance, cell survival, cell self-renewal. On the other hand, Over-expression of versican and TGF-β promote osteoblast cells expressing enhanced EGFR/JNK, which inhibits osteoblast cell differentiation. Elevated expression levels of versican and TNF-α in bone stroma activate pEGFR /pJNK signaling in osteoblast cells, which induces ostoblast cells apoptosis. Versican and TGF-β related inhibited of ostoblast growth may partially releted to downregulated expression of GSK-3β (S9P). In summary, versican enhances breast cancer bone metastasis not only by enhancing tumor cell mobility, invasion, and survival in bone tissues, but also via inhibiting osteoblast cell growth, differentiation, which supply favorable microenvironments for tumor metastasis.