Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2 - Both ErbB-1 and ErbB-2 contribute significantly to tumorigenicity

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 nontumoringenic cells overexpressing ErbB-2 endogenously produced high levels of transforming growth factor (TGF)-alpha, and that reducing TGF-alpha by 93% eliminated tumorigcnicity. In the present report, comparison of ErbB species between the tumorigenic cells (E6T) and their nontumorigenic derivatives (EGTA) demonstrated all four receptors in both cell types, However, in EGTA 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 tumorige nicity, whereas ErbB-2 internalization was selected against during tumor formation. These data demonstrate the importance of TGF-alpha-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-alpha. Fernandes, A. M., A. W. Hamburger, and B. I. Gerwin. 1999. Dominance of ErbB-1 heterodimers in lung epithelial cells overexpressing ErbB-2: both ErtiB-1 and ErbB-2 contribute significantly to tumorigenicity.