Journal
MOLECULAR CANCER
Volume 11, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1476-4598-11-79
Keywords
EGF; IL-1 beta; ERK1/2; Invasive breast ductal carcinoma; BT-474 cells; Metastasis; MMP-9; AP-1
Categories
Funding
- Medical Scientific Research Key Foundation of Nanjing Command [11Z032]
- Natural Science Foundation of Fujian Province [2009J01181]
- Medical Scientific Research Foundation of Nanjing Command [08 MA100]
- Fuzhou General Hospital Special Foundation [2004037]
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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)-1 beta 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-1 beta, MMP-9 and c-fos in IBDC tissue samples. Co-stimulation with EGF and IL-1 beta 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-1 beta-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.
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