Expression of ErbB2 enhances radiation-induced NF-κB activation

Guozheng Guo, Tieli Wang, Qian Gao, Daniel Tamae, Patty Wong, Tammy Chen, Wei Chung Chen, John E. Shively, Jeffery Y.C. Wong, Jian Jian Li

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Her-2/neu (ErbB2) oncogene, the second member of the epidermal growth factor receptor (EGFR) family, encodes a transmembrane tyrosine kinase receptor in Her-2-positive tumors. Accumulating evidences demonstrate that signaling networks activated by EGFR and transcription factor NF-κB are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF-κB activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant IκB (MCF-7/ErbB2/mIκB) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF-κB activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF-κB regulation, basal and IR-induced Akt, a kinase downstream of ErbB2, was activated in MCF-7/ ErbB2 cells and inhibited by Herceptin. To identify specific genes affected by ErbB2-mediated NF-κB activation, a group of IR-responsive elements Cyclin B1, Cyclin D1, Bcl-2, Bcl/XL, BAD and BAX were evaluated. Basal levels of prosurvival elements Cyclin B1, Cyclin D1, Bcl-2 and Bcl/XL but not apoptotic BAD and BAX were upregulated in MCF-7/ErbB2 cells with striking enhancements in Bcl-2 and Bcl/XL. IR further induced Cyclin B1 and Cyclin D1 expression that was reduced by Herceptin. Bcl-2 kept a high steady level after Herceptin+IR treatment and, in contrast to control MCF-7/Vector cells, Bcl/XL was inhibited in MCF-7/ErbB2 cells by Herceptin+IR treatment. However, all four prosurvival proteins were down-regulated by inhibition of NF-κB in MCF-7/ErbB2/mIκB cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF-κB response to IR, and that a specific prosurvival network downstream of NF-κB is triggered by treatments using anti-ErbB2 antibody combined with radiation.

Original languageEnglish
Pages (from-to)535-545
Number of pages11
Issue number2
StatePublished - 15 Jan 2004
Externally publishedYes


  • Breast cancer
  • ErbB2
  • NF-κB
  • Radioresistance


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