Dominant negative interference of transcription factor AP-2 causes inhibition of ErbB-3 expression and suppresses malignant cell growth

Abstract

ErbB-3 (HER3) is a member of the epidermal growth factor receptor family. Increasing evidence suggests that elevated expression of ErbB-3 is important for malignancy. In this study, we found that elevated levels of ErbB-3 expression did not occur in the absence of AP-2γ in a panel of human mammary epithelial and fibroblasts cell lines. In contrast, there was no association between the expression of AP-2α or AP-2β and the level of ErbB-3, or between AP-2α and AP-2γ double positivity and ErbB-3 expression. In co-transfection experiments, exogenous expression of AP-2γ robustly activated ErbB-3 promoter activity. Moreover, expression of a dominant negative AP-2 protein, AP-2A (deleted residues 31-117), not only repressed the ErbB-3 promoter activity but also suppressed endogenous ErbB-3 transcription in the ErbB-3 overexpressing cell line MRC-5VA. Overexpression of AP-2A resulted in a decreased proliferation rate and inhibition of colony formation. Taken together, these data strongly support a role for the AP-2 gene family, in particular, AP-2γ, in the control of ErbB-3 expression. Interference with the function of transcription factor AP-2 might provide a potential strategy for modulation of the malignant phenotype.