Breast cancer is one of the most common malignancies in women and represents 22.9% of all female cancers worldwide . Although 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 processes by which metastasis occurs in breast cancer are still poorly understood; therefore, characterization of the precise molecular mechanisms that regulate metastasis in breast cancer could potentially result in a large reduction in the number of breast cancer deaths and may lead to novel treatments for breast cancer.
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]. Five ERK homologs have been identified: ERK1, ERK2, ERK5, ERK7 and ERK8 [5, 6]. It is well established that ERK1 and ERK2 are two of the most important regulators of cell proliferation, growth, differentiation and migration [7, 8], and these processes are closely related to cancer cell progression. MAPK is activated by the upstream MAP2K kinases, which in turn are activated by the MAP3K kinases. To date, 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 .
ERK1/2 activation has been observed in a wide variety of cancers, and is closely associated with the development of human cancer and also with the migration, invasion and metastasis of cancer cells . Therefore, the ERK1/2 signaling pathways are regarded as potential targets for new cancer treatments . ERK1/2 is frequently activated by growth factors, such as epidermal growth factor (EGF), which leads to increased cell growth, differentiation and migration. Although the EGF/Raf/MEK1/2/ERK1/2 pathway has been investigated with respect to cancer cell metastasis, and it is known that the activation of ERK1/2 promotes the growth of breast cancer cells , the effect of ERK1/2 signaling activation on the metastasis of invasive breast ductal carcinoma is poorly characterized and remains of interest.
Recently, increasing attention has been paid to the tumor microenvironment, which has been closely associated with carcinogenesis and metastasis [13, 14]. Accumulating evidence demonstrates that the cytokines secreted by tumor cells are important components of the tumor microenvironment. Interleukin (IL)-1β can activate ERK1/2 in several different cell types, and can also activate the transcription factor activator protein (AP)-1, which may promote inflammation-associated carcinogenesis and play a role in cancer metastasis . However, the effects of ERK1/2 signaling in IL-1β-induced inflammation-associated metastasis, and the synergistic effect of both growth and inflammatory factors on metastasis in IBDC, have not been well studied.
In this study, the roles of ERK1/2 in IBDC metastasis, and the function of EGF and IL-1β-induced ERK1/2-mediated signaling, were investigated in IBDC cells. We observed that activated phosphorylated ERK1/2 was associated with a higher TNM stage and the presence of lymph node metastasis in IBDC. Additionally, in vitro studies indicated that the activation of ERK-1/2 may increase the metastatic ability of IBDC cells, and in vivo investigations in IBDC tissue samples showed that the expression of p-ERK1/2 had good levels of correlation with the levels of EGF in addition to IL-1β, matrix metalloproteinase (MMP-9) and c-fos (AP-1). Growth and inflammatory factors synergistically induced IBDC cell migration and invasion via activation of the ERK1/2 signaling pathway, leading to the activation of AP-1 and increased matrix MMP-9 expression and activity.