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J. Biol. Chem., Vol. 280, Issue 47, 39273-39277, November 25, 2005

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Erythropoietin Promotes MCF-7 Breast Cancer Cell Migration by an ERK/Mitogen-activated Protein Kinase-dependent Pathway and Is Primarily Responsible for the Increase in Migration Observed in Hypoxia^*

Robin D. Lester, Minji Jo, W. Marie Campana, and Steven L. Gonias1

From the Departments of Pathology and Anesthesiology, University of California San Diego, La Jolla, California 92093

Recent studies indicate that cancer cells express erythropoietin receptor (EpoR). In this study, we have shown that erythropoietin (Epo) activates the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and promotes migration in MCF-7 breast cancer cells. Epo-stimulated MCF-7 cell migration was blocked by the MEK inhibitor PD098059 and by dominant negative MEK-1, indicating an essential role for ERK. When MCF-7 cells were exposed to hypoxia (1.0% O₂) for 3 h, the Epo mRNA level increased 2.4 ± 0.5-fold, the basal level of ERK activation increased, and cell migration increased 2.0 ± 0.1-fold. Soluble EpoR and Epo-neutralizing antibody significantly inhibited hypoxia-induced MCF-7 cell migration, suggesting a major role for autocrine EpoR cell signaling. MCF-7 cell migration under hypoxic conditions was also inhibited by PD098059. These experiments identify a novel pathway by which exogenously administered Epo, and Epo that is produced locally by cancer cells under hypoxic conditions, may stimulate cancer cell migration.

Received for publication, August 26, 2005

^* This work was supported by National Institutes of Health Grants R01 CA-94900 (to S. L. G.) and R01 NS-41983 (to W. M. C.). 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.

¹ To whom correspondence should be addressed. Tel.: 858-534-1887; Fax: 858-534-0414; E-mail: sgonias{at}ucsd.edu.

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