Abstract
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% O(2)) 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.
Highlights
In adults, Epo is produced mainly by peritubular fibroblasts in the kidney; diverse cells in multiple organs express Epo [5]
The Epo mRNA level and the basal level of extracellular signal-regulated kinase (ERK) activation are increased. These changes are accompanied by an increase in the rate of MCF-7 cell migration, which is significantly inhibited by Epo-neutralizing antibody, soluble erythropoietin receptor (EpoR), and by the MEK inhibitor, PD098059
Epo Activates ERK in Breast Cancer Cells—MCF-7 breast cancer cells typically demonstrate limited motility; agents that have been implicated in breast cancer progression, including urokinase-type plasminogen activator, epidermal growth factor, and heregulin activate ERK in MCF-7 cells and promote MCF-7 cell migration [25, 27, 28]
Summary
Antibodies and Reagents—Recombinant human Epo (287-TC), recombinant human EpoR (963ER), and Epo-neutralizing antibody 287 were obtained from R&D Systems, Inc. (Minneapolis, MN). The MEK inhibitor, NOVEMBER 25, 2005 VOLUME 280 NUMBER 47
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