Am. J. Respir. Cell Mol. Biol.,
Volume 21, Number 6, December, 1999 701-709
Dominance of ErbB-1 Heterodimers in Lung Epithelial Cells
Overexpressing ErbB-2
Both ErbB-1 and ErbB-2 Contribute Significantly to Tumorigenicity
Audrey M.
Fernandes,
Anne W.
Hamburger,
and
Brenda I.
Gerwin
Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda; and University of Maryland Cancer Center
and Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
This article examines differential expression and heterodimer formation of ErbB family members in tumorigenic and nontumorigenic human bronchial epithelial cells (HBECs). This cell system was developed
previously as a model for lung adenocarcinoma by overexpression of c-erbB-2 in nontumorigenic, T antigen-immortalized HBECs. Earlier studies demonstrated that a tumorigenic clone from T antigen-immortalized nontumorigenic cells overexpressing ErbB-2 endogenously produced high levels of transforming
growth factor (TGF)-
, and that reducing TGF- by 93% eliminated tumorigenicity. In the present report, comparison of ErbB species between the tumorigenic cells (E6T) and their nontumorigenic derivatives
(E6TA) demonstrated all four receptors in both cell types. However, in E6TA cells, ErbB-3 and -4 were
present primarily in ErbB-1 heterodimers, suggesting that ErbB-1 is a preferred heterodimer partner within
this cell system, expressing endogenous ErbB receptors and ligands and overexpressing ErbB-2. The
ErbB-1/-2 species was present at high levels in E6T and absent in E6TA cells. Mitogen-activated protein
kinase activity was elevated in E6T relative to E6TA. Elevated activity was eliminated by blocking surface
expression of either ErbB-1 or ErbB-2. Endoplasmic reticulum trapping of ErbB-1 eliminated tumorigenicity, whereas ErbB-2 internalization was selected against during tumor formation. These data demonstrate the importance of TGF--mediated signaling through the ErbB-1/-2 heterodimer in development of
the tumorigenic phenotype. This work further suggests that ErbB-3 and -4 species may also contribute to
tumorigenic conversion and that their expression levels may be increased by signaling initiated by TGF-.
