CCN6 (WISP3) as a new regulator of the epithelial phenotype in breast cancer.

CCN6 (WISP3) is a cysteine-rich secreted protein that belongs to the CCN (Cyr61, CTGF, Nov) family of genes. We found that CCN6 mRNA is reduced in 80% of cases of the most lethal form of locally advanced breast cancer, inflammatory breast cancer. CCN6 contains four highly conserved motifs with sequence similarities to insulin-like growth factor binding proteins, von Willebrand type C, thrombospondin 1, and a carboxyl-terminal domain putatively involved in dimerization. CCN6 has tumor growth-, proliferation-, and invasion-inhibitory functions in breast cancer. Recently, by using a small infering RNA to downregulate CCN6 in immortalized human mammary epithelial cells, CCN6 was found to be essential to induce the process of epithelial-mesenchymal transition (EMT) with repression of E-cadherin gene expression and induction of a protein expression program characteristic of EMT. This review will focus on the current knowledge regarding the function of CCN6 in breast cancer with special emphasis on the emerging role of CCN6 as a regulator of the epithelial phenotype and E-cadherin expression in the breast.