Expression of ErbB2 enhances radiation-induced NF- κ B activation
Oncogene(2004)
Abstract
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- κ B are associated with cell response to ionizing radiation (IR). The present study shows that overexpression of ErbB2 enhanced NF- κ B activation induced by IR in human breast carcinoma MCF-7 cells transfected with ErbB2 genes (MCF-7/ErbB2). Stable transfection of dominant-negative mutant I κ B (MCF-7/ErbB2/mI κ B) or treatment with anti-ErbB2 antibody, Herceptin, inhibited NF- κ B activation and radiosensitized MCF-7/ErbB2 cells. Consistent with NF- κ B 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- κ B 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 downregulated by inhibition of NF- κ B in MCF-7/ErbB2/mI κ B cells. These results thus provide evidence suggesting that overexpression of ErbB2 is able to enhance NF- κ B response to IR, and that a specific prosurvival network downstream of NF- κ B is triggered by treatments using anti-ErbB2 antibody combined with radiation.
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Key words
NF-κB,ErbB2,breast cancer,radioresistance
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