Inhibition of CCN6 (WISP3) expression promotes neoplastic progression and enhances the effects of insulin-like growth factor-1 on breast epithelial cells

Breast Cancer Res. 2005;7(6):R1080-9. doi: 10.1186/bcr1351. Epub 2005 Nov 8.


Introduction: CCN6/WISP3 belongs to the CCN (Cyr61, CTGF, Nov) family of genes that contains a conserved insulin-like growth factor (IGF) binding protein motif. CCN6 is a secreted protein lost in 80% of the aggressive inflammatory breast cancers, and can decrease mammary tumor growth in vitro and in vivo. We hypothesized that inhibition of CCN6 might result in the loss of a growth regulatory function that protects mammary epithelial cells from the tumorigenic effects of growth factors, particularly IGF-1.

Method: We treated human mammary epithelial (HME) cells with a CCN6 hairpin short interfering RNA.

Results: CCN6-deficient cells showed increased motility and invasiveness, and developed features of epithelial-mesenchymal transition (EMT). Inhibition of CCN6 expression promoted anchorage-independent growth of HME cells and rendered them more responsive to the growth effects of IGF-1, which was coupled with the increased phosphorylation of IGF-1 receptor and insulin receptor substrate-1 (IRS-1).

Conclusion: Specific stable inhibition of CCN6 expression in HME cells induces EMT, promotes anchorage-independent growth, motility and invasiveness, and sensitizes mammary epithelial cells to the growth effects of IGF-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast / cytology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / physiopathology
  • CCN Intercellular Signaling Proteins
  • Cell Movement
  • Cell Transformation, Neoplastic / genetics*
  • Disease Progression
  • Down-Regulation
  • Epithelial Cells
  • Female
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / biosynthesis*
  • Insulin-Like Growth Factor Binding Proteins / genetics
  • Insulin-Like Growth Factor I / physiology*
  • Mammary Glands, Human / cytology
  • Mesoderm / cytology
  • Neoplasm Invasiveness
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction


  • CCN Intercellular Signaling Proteins
  • CCN6 protein, human
  • Insulin-Like Growth Factor Binding Proteins
  • Neoplasm Proteins
  • Insulin-Like Growth Factor I