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Epidermal growth factor (EGF) and interleukin (IL)-1β synergistically promote ERK1/2-mediated invasive breast ductal cancer cell migration and invasion

Liqiang Ma1, Fenghua Lan1, Zhiyong Zheng2, Feilai Xie2, Lie Wang3, Wei Liu2, Junyong Han1, Feng Zheng4, Yanchuan Xie1 and Qiaojia Huang1*

Author Affiliations

1 Institute for Laboratory Medicine, Fuzhou General Hospital, Second Military Medical University, 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, China

2 Department of Pathology, Fuzhou General Hospital, Second Military Medical University, 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, China

3 Department of General Surgery, Fuzhou General Hospital, Second Military Medical University, 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, China

4 Department of Nephrology, Fuzhou General Hospital, Second Military Medical University, 156 North Xi-er Huan Road, Fuzhou City, Fujian Province, 350025, China

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Molecular Cancer 2012, 11:79  doi:10.1186/1476-4598-11-79

Published: 21 October 2012

Abstract

Background

Patients with invasive breast ductal carcinoma (IBDC) with metastasis have a very poor prognosis. Little is known about the synergistic action of growth and inflammatory factors in IBDC metastases.

Methods

The expression of activated extracellular signal-regulated kinase1/2 (phosphorylated or p-ERK1/2) was analyzed by immunohistochemistry in IBDC tissue samples from 80 cases. BT474 IBDC cell migration and invasion were quantified using the Transwell assay. Matrix metalloproteinase (MMP)-9 expression and activity were analyzed by RT-PCR, Western blotting and zymography. Activator protein (AP)-1 activity was measured with a luciferase reporter gene assay. The Wilcoxon signed-rank test, Chi-square test, the partition of Chi-square test, independent t-test, and Spearman’s method were used for the statistical analysis.

Results

Phosphorylated ERK1/2 was detected in 58/80 (72.5%) IBDC tissues, and was associated with higher TNM stage and lymph node metastasis, but not patient age or tumor size. Individually, epidermal growth factor (EGF), and interleukin (IL)-1β activated ERK1/2, increased cell migration and invasion, MMP-9 expression and activity, AP-1 activation in vitro and the expression of p-ERK1/2 was positively correlated with EGF expression levels, as well as IL-1β, MMP-9 and c-fos in IBDC tissue samples. Co-stimulation with EGF and IL-1β synergistically increased ERK1/2 and AP-1 activation, cell migration and invasion, and MMP-9 expression and activity. Inhibition of ERK1/2 using U0126 or siRNA abolished EGF and/or IL-1β-induced cell migration and invasion in a dose-dependent manner.

Conclusion

Activated ERK1/2 was associated with higher TNM stage and lymph node metastasis in IBDC. Both in vitro and in vivo studies indicated that ERK-1/2 activation may increase the metastatic ability of IBDC cells. Growth and inflammatory factors synergistically induced IBDC cell migration and invasion via ERK1/2 signaling, AP-1 activation and MMP-9 upregulation.

Keywords:
EGF; IL-1β; ERK1/2; Invasive breast ductal carcinoma; BT-474 cells; Metastasis; MMP-9; AP-1