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


METHODS
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).


CONCLUSIONS
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.
Zhang
Yanhong
Y
Department of Pathology, University of Michigan Medical Center, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA. zhangyan@umich.edu
Pan
Quintin
Q
Zhong
Hui
H
Merajver
Sofia D
SD
Kleer
Celina G
CG
D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D055511:CCN Intercellular Signaling Proteins; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D015536:Down-Regulation; D004847:Epithelial Cells; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D042361:Mammary Glands, Human / Q000166:cytology; D008648:Mesoderm / Q000166:cytology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
D055511:CCN Intercellular Signaling Proteins; C400081:CCN6 protein, human; D018969:Insulin-Like Growth Factor Binding Proteins; D009363:Neoplasm Proteins; D007334:Insulin-Like Growth Factor I