title: Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression.
abstract: Cell migration is a critical step in cancer cell invasion. Recent studies have implicated the importance of the extracellular signal-regulated kinase (ERK) signaling pathway in cancer cell migration. However, the mechanism associated with ERK-regulated cell migration is poorly understood. Using a panel of breast cancer cell lines, we detected an excellent correlation between ERK activity and cell migration. Interestingly, we noticed that a 48-hour treatment with U0126 [specific mitogen-activated protein/ERK kinase (MEK)-1/2 inhibitor] was needed to significantly inhibit breast cancer cell migration, whereas this inhibitor blocked ERK activity within 1 hour. This observation suggests that ERK-dependent gene expression, rather than direct ERK signaling, is essential for cell migration. With further study, we found that ERK activity promoted the expression of the activator protein-1 (AP1) components Fra-1 and c-Jun, both of which were necessary for cell migration. Combination of U0126 treatment and Fra-1/c-Jun knockdown did not yield further reduction in cell migration than either alone, indicating that ERKs and Fra-1/c-Jun act by the same mechanism to facilitate cell migration. In an attempt to investigate the role of Fra-1/c-Jun in cell migration, we found that the ERK-Fra-1/c-Jun axis regulated slug expression in an AP1-dependent manner. Moreover, the occurrence of U0126-induced migratory inhibition coincided with slug reduction, and silencing slug expression abrogated breast cancer cell migration. These results suggest an association between ERK-regulated cell migration and slug expression. Indeed, cell migration was not significantly inhibited by U0126 treatment or Fra-1/c-Jun silencing in cells expressing slug transgene. Our study suggests that the ERK pathway regulates breast cancer cell migration by maintaining slug expression.
authors.affiliation: Department of Biochemistry, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Haoming
authors.initials: H
authors.lastname: Chen
authors.forename: Genfeng
authors.initials: G
authors.lastname: Zhu
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Ravi N
authors.initials: RN
authors.lastname: Padia
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Zhixing K
authors.initials: ZK
authors.lastname: Pan
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D020935:MAP Kinase Signaling System; D051379:Mice; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000099169:Fos-Related Antigen 1
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C113580:U 0126