Abstract
BackgroundPatients 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.MethodsThe 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.ResultsPhosphorylated 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.ConclusionActivated 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.
Highlights
Patients with invasive breast ductal carcinoma (IBDC) with metastasis have a very poor prognosis
The expression of p-ERK1/2 was not correlated with patient age or tumor size; the expression of p-ERK1/2 was closely associated with higher TNM stage and lymph node metastasis in IBDC (Table 1)
This study demonstrates that the expression of p-ERK1/ 2 in IBDC is closely related to lymph node metastasis and high tumor grade, which are indicative of poor patient prognosis
Summary
Patients with invasive breast ductal carcinoma (IBDC) with metastasis have a very poor prognosis. The 5-year survival rates for breast cancer throughout the world are generally good [1,2], the prognosis for patients with metastases is very poor, especially in metastatic invasive breast ductal carcinoma (IBDC). The mitogen-activated protein kinase (MAPK) signaling pathways have been widely studied, and contain at least three MAPK superfamilies that regulate diverse cellular activities. Extracellular signal-regulated kinase (ERK) is the most essential MAPK signaling pathway and is involved in cell growth, motility and survival [3,4]. Several MAP3Ks and MAP2Ks have been identified that regulate the ERK signaling pathway, including the MAP3Ks Raf and Mos, and the MAP2Ks, MAPK/ ERK kinase 1 (MEK1) and MEK2. ERK1/2 is a direct target of MEK1 and MEK2 [9]
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