title: 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.
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.
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Robin D
authors.initials: RD
authors.lastname: Lester
authors.forename: Minji
authors.initials: M
authors.lastname: Jo
authors.forename: W Marie
authors.initials: WM
authors.lastname: Campana
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology*; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009500:Neutralization Tests; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins
chemical_list: D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one