Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-12, Vol.69 (24), p.9228-9235
• Main Authors: Chen, Haoming, Zhu, Genfeng, Li, Yong, Padia, Ravi N, Dong, Zheng, Pan, Zhixing K, Liu, Kebin, Huang, Shuang
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Butadienes - pharmacology; Cell Line, Tumor; Cell Movement - physiology; Enzyme Inhibitors - pharmacology; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - secondary; MAP Kinase Signaling System; Mice; Neoplasm Invasiveness; Nitriles - pharmacology; Oligonucleotide Array Sequence Analysis; Phosphorylation; Proto-Oncogene Proteins c-fos - biosynthesis; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - biosynthesis; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; RNA, Small Interfering - genetics; Snail Family Transcription Factors; Transcription Factors - biosynthesis; Transcription Factors - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-1950

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.