M. Santra et al., An anti-oncogenic role for decorin - Down-regulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells, J BIOL CHEM, 275(45), 2000, pp. 35153-35161
The leucine-rich proteoglycan decorin interacts with the epidermal growth f
actor receptor and triggers a signaling pathway that leads to growth suppre
ssion. We find that decorin causes a functional inactivation of the oncogen
ic ErbB2 protein in breast carcinoma cells. Upon de novo expression of deco
rin, the ErbB2 protein is reduced by similar to 40%, whereas its degree of
tyrosyl phosphorylation is almost completely abrogated. Both co-culture exp
eriments or experiments with recombinant decorin demonstrate an initial ind
uction of ErbB2 tyrosine kinase, followed by a profound and long-lasting do
wnregulation of its activity. This leads to growth inhibition and cytodiffe
rentiation of mammary tumor cells and a concurrent suppression of their tum
origenic potential in vivo. These decorin-mediated effects appear to involv
e the activation of ErbB4, which in turn would block the phosphorylation of
heterodimers containing either ErbB2 or ErbB3. These results provide an ex
planation for the heightened decorin levels around invasive carcinomas and
suggest that decorin may function as a natural antagonist of neoplastic cel
ls enriched in ErbB2.