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J. Biol. Chem., Vol. 283, Issue 2, 739-750, January 11, 2008

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Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells^*

Niels Eckstein, Kati Servan, Luc Girard, Di Cai, Georg von Jonquieres, Ulrich Jaehde^¶, Matthias U. Kassack^||, Adi F. Gazdar, John D. Minna¹, and Hans-Dieter Royer²

From the Stiftung Center of Advanced European Studies and Research, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593, the ^¶Department of Clinical Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany, and ^||Pharmaceutical Biochemistry, Institute of Pharmaceutical and Medicinal Chemistry, University of Duesseldorf, Universitaetsstrasse 1, 40225 Duesseldorf, Germany

The use of platinum complexes for the therapy of breast cancer is an emerging new treatment modality. To gain insight into the mechanisms underlying cisplatin resistance in breast cancer, we used estrogen receptor-positive MCF-7 cells as a model system. We generated cisplatin-resistant MCF-7 cells and determined the functional status of epidermal growth factor receptor (EGFR), MAPK, and AKT signaling pathways by phosphoreceptor tyrosine kinase and phospho-MAPK arrays. The cisplatin-resistant MCF-7 cells are characterized by increased EGFR phosphorylation, high levels of AKT1 kinase activity, and ERK1 phosphorylation. In contrast, the JNK and p38 MAPK modules of the MAPK signaling pathway were inactive. These conditions were associated with inactivation of the p53 pathway and increased BCL-2 expression. We investigated the expression of genes encoding the ligands for the ERBB signaling cascade and found a selective up-regulation of amphiregulin expression, which occurred at later stages of cisplatin resistance development. Amphiregulin is a specific ligand of the EGFR (ERBB1) and a potent mitogen for epithelial cells. After exposure to cisplatin, the resistant MCF-7 cells secreted amphiregulin protein over extended periods of time, and knockdown of amphiregulin expression by specific short interfering RNA resulted in a nearly complete reversion of the resistant phenotype. To demonstrate the generality and importance of our findings, we examined amphiregulin expression and cisplatin resistance in a variety of human breast cancer cell lines and found a highly significant correlation. In contrast, amphiregulin levels did not significantly correlate with cisplatin resistance in a panel of lung cancer cell lines. We have thus identified a novel function of amphiregulin for cisplatin resistance in human breast cancer cells.

Received for publication, July 31, 2007 , and in revised form, October 10, 2007.

^* This work was supported in part by Deutsche Forschungsgemeinschaft Grant GRK 677/3 and the University of Bonn. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by NCI Grant NCI SPORE P50CA70907 from the National Institutes of Health and The Pulitzer Foundation.

² To whom correspondence should be addressed. Tel.: 49-228-9656-168; E-mail: royer{at}caesar.de.

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