Breast cancer is one of the leading causes of cancer-related death in women worldwide. The difficulties in breast cancer treatment are attributed to the highly metastatic ability of breast cancer cells. Serum interleukin-6 (IL-6) level increases with tumor grade of breast cancer, and elevated serum IL-6 correlates with poor breast cancer patient survival. In addition, the aberrant activation of epithelial-mesenchymal transition (EMT) has been implicated in the enhanced tumor metastasis. Recently, IL-6 has been shown to induce EMT in breast cancer cells with an epithelial phenotype. However, the underlying mechanisms by which IL-6 induces EMT remain to be fully defined.
In this study, we explored the underlying mechanisms of IL-6 in inducing EMT in MCF-7 breast cancer cells.
Treatment of MCF-7 cells with IL-6 results in EMT, as evidenced by induction of the mesenchymal markers twist and snail and repression of the epithelial marker E-cadherin. IL-6 also increased cell motility in MCF-7 cells. These actions were associated with Src and FAK activation, as well as the phosphorylation of STAT3, p65 and C/EBPÃ. Src-FAK signaling blockade reduced IL-6's actions on the phosphorylation of STAT3, p65 and C/EBPÃ and subsequent EMT. In addition, STAT3 knockdown by STAT3 siRNA suppressed IL-6-induced EMT. Furthermore, IL-6 caused increases in STAT3, p65 and C/EBPÃ binding to the twist promoter region in MCF-7 cells.
In conclusion, we demonstrated in this study that IL-6 may activate Src-FAK-STAT3 signaling cascade, leading to EMT and subsequent breast cancer metastasis. Transcription factors p65 and C/EBPÃ may also contribute to IL-6-induced EMT in MCF-7 cells.
Clinical trial identification
All authors have declared no conflicts of interest.