Interleukin-8 upregulates integrin β3 expression and promotes estrogen receptor-negative breast cancer cell invasion by activating the PI3K/Akt/NF-κB pathway

Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties and is overexpressed in many human cancers. The integrin family regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumors. However, the mechanisms of action of IL-8 and integrin in estrogen receptor-negative breast cancer are largely unknown. In this study, IL-8 and integrin beta 3 expression in human breast cancer cells and tissues was examined by real-time PCR, Western blot and immunochemistry analysis. Integrin beta 3 expression, invasive ability and the activation of PI3K/Akt and NF-kappa B pathways in IL-8 knockdown breast cancer cells were evaluated. In addition, reporter assay and ChIP were performed to assess integrin beta 3 promoter activity in IL-8 knockdown cells. We observed a positive correlation between integrin beta 3 and IL-8 expression, which was inversely correlated with ER status in breast cancer cell lines and tissues. IL-8 siRNA decreased the invasion and integrin beta 3 expression in human breast cancer cells. Moreover, IL-8 siRNA attenuated the phosphorylation of PI3K and Akt and inhibited NF-kappa B activity and binding on integrin beta 3 promoter. IL-8 siRNA diminished NF-kappa B nuclear translocation via blocking I kappa B phosphorylation in the cytoplasm. In conclusion, IL-8 activates the PI3K/Akt pathway, which in turn activates NF-kappa B, resulting in the upregulation of integrin beta 3 expression and increased invasion of estrogen receptor-negative breast cancer cells. IL-8/PI3K/Akt/NF-kappa B/integrin beta 3 axis may be exploited for therapeutic intervention to breast cancer metastasis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.