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

Authors: Zhu C-H.; Domann F.E.

Source: Breast Cancer Research and Treatment, Volume 71, Number 1, January 2002 , pp. 47-57(11)

Publisher: Springer

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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-2 gamma in a panel of human mammary epithelial and fibroblasts cell lines. In contrast, there was no association between the expression of AP-2 alpha or AP-2 beta and the level of ErbB-3, or between AP-2 alpha and AP-2 gamma double positivity and ErbB-3 expression. In co-transfection experiments, exogenous expression of AP-2 gamma robustly activated ErbB-3 promoter activity. Moreover, expression of a dominant negative AP-2 protein, AP-2Delta; (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-2 Delta 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-2 gamma , 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.

Keywords: activator protein-2; breast cancer; epidermal growth factor receptor; heregulin; neuregulin

Language: English

Document Type: Regular paper

Affiliations: 1: Free Radical & Radiation Biology Program, Department of Radiation Oncology, and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242

Publication date: 2002-01-01