Abstract
BackgroundThe elevated production of interleukin (IL)–8 is critically associated with invasiveness and metastatic potential in breast cancer cells. However, the intracellular signaling pathway responsible for up-regulation of IL-8 production in breast cancer cells has remained unclear.Methodology/Principal FindingsIn this study, we report that the expression of BLT2 is markedly up-regulated in the highly aggressive human breast cancer cell lines MDA-MB-231 and MDA-MB-435 compared with MCF-10A immortalized human mammary epithelial cells, as determined by RT-PCR, real-time PCR and FACS analysis. Blockade of BLT2 with BLT2 siRNA knockdown or BLT2 inhibitor treatment downregulated IL-8 production and thereby diminished the invasiveness of aggressive breast cancer cells, analyzed by Matrigel invasion chamber assays. We further characterized the downstream signaling mechanism by which BLT2 stimulates IL-8 production and identified critical mediatory roles for the generation of reactive oxygen species (ROS) and the consequent activation of the transcription factor NF-κB. Moreover, blockade of BLT2 suppressed the formation of metastatic lung nodules by MDA-MB-231 cells in both experimental and orthotopic metastasis models.Conclusions/SignificanceTaken together, our study demonstrates that a BLT2–ROS–NF-κB pathway up-regulates IL-8 production in MDA-MB-231 and MDA-MB-435 cells, thereby contributing to the invasiveness of these aggressive breast cancer cells. Our findings provide insight into the molecular mechanism of invasiveness in breast cancer.
Highlights
Cancer invasion is a fundamental aspect of metastasis and is the major cause of death in cancer patients [1]
We examined the effect of LY255283 on the metastatic potential of aggressive breast cancer cells in an orthotopic metastasis assay in which MDA-MB231 cells were implanted into the mammary fat pad
We have found that the expression level of BLT2 is markedly increased in the highly aggressive breast cancer cell lines MDA-MB-231 and MDA-MB-435
Summary
Cancer invasion is a fundamental aspect of metastasis and is the major cause of death in cancer patients [1]. Interleukin (IL)-8 has recently been suggested to promote the invasive and metastatic potential of breast cancer cells. Increased levels of IL-8 were detected in breast cancer cells with a highly invasive phenotype [4], and the expression of IL-8 was found to correlate with the progression of metastasis in breast cancer cells [5,6]. Despite the importance of IL-8 in cancer invasion and metastasis, the cellular signals required for the production of IL-8 in breast cancer cells have remained unknown. The elevated production of interleukin (IL)–8 is critically associated with invasiveness and metastatic potential in breast cancer cells. The intracellular signaling pathway responsible for up-regulation of IL-8 production in breast cancer cells has remained unclear
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