Function of Cyr61 and CTGF in cell adhesive signaling, gene expression, wound healing and breast cancer

Both Cyr61 and CTGF are members of the CCN gene family of secreted proteins, and are critical for embryonic blood vessel integrity and skeleton development, respectively. Both can induce fibroblast attachment via integrin α6β1 and cell surface heparan sulfate proteoglycans, leading to actin re-organization, and filopodia, lamellipodia and focal complexes formation. Besides activating focal adhesion kinase and Rac, both Cyr61 and CTGF causes prolonged p42/p44 MAP kinase activation as well. Thus Cyr61 and CTGF are genuine extracellular matrix (ECM) signaling proteins. Using cDNA micro-array and RNA blotting, I showed exposure of skin fibroblasts to Cyr61 leads to elevation of integrin α3 and α5 subunits, VEGF-A, VEGF-C, IL-1β, MMP1, MMP3, TIMP-1, uPA, and PAI-1 expression, and suppression of type 1 collagen expression. With an animal model of wound healing, I showed cyr61 is highly induced during skin wound repair. Moreover, I found human mammary adenocarcinoma cells MCF7 can secret factors to enhance fibroblast CYR61 expression. In a MCF7 cells-fibroblasts co-transplantation experiment, cyr61−/− fibroblasts didn't promote MCF7 cell-derived tumor growth in nude mice, in contrast to cyr61+/+ fibroblasts. Concordantly, recent reports show CYR61 is induced in human breast cancer biopsies. In conclusion, as an ECM-signaling protein, Cyr61 is involved in cancer cell-fibroblast interaction, and may act on fibroblasts to coordinate angiogenesis, inflammation and ECM-remodeling to promote breast cancer growth and wound healing.