Effect And Underlying Mechanism Of CXCL1 On Migration And Invasion In ER Negative Breast Cancer Cells

Objective: To investigate the effect of the high expression of CXCL1 on migration and invasion in ER-negative breast cancer cells,and further explore its intrinsic signal transduction mechanism,providing a new experimental evidence for the treatment strategy of ER-negative breast cancer.Methods: The expression of CXCL1 mRNA in 87 cases of breast cancer(32 cases of ER-positive breast cancer and 55 cases of ER-negative breast cancer)was detected by qRT-PCR.Expression levels of CXCL1 were analyzed in breast cancer cell lines using qRT-PCR,ELISA,and immunofluorescence assays.Transwell assay was used to detect the effects of rhCXCL1 on MDA-MB-231 and BT-549 cells migration and invasion.Western Blot was used to detect the expression of key proteins in the PI3K/AKT,JAK/STAT3 and ERK1/2 pathways after rhCXCL1 treatment on ER-negative breast cancer cells.The cells were treated with SB225002(a specific inhibitor of CXCR2)and U0126(a blocker of ERK1/2 pathway),and the underlying molecular mechanisms of the effects of CXCL1 on themigration and invasion of ER-negative breast cancer were detected by Transwell and Western Blot assays.Finally,we used immunohistochemistry to analyze the expression and correlation of CXCL1 and p-ERK1/2 proteins in paraffin sections from 88 breast cancer patients.Results: We discovered that CXCL1 is overexpression in ER-negative breast cancer tissues and cell lines compared with ER-positive patient tissues and cell lines.Treatment with recombinant human CXCL1 protein promotes ER-negative BC cell migration and invasion in dose-dependent manner and stimulates the activation of p-ERK1/2,but not p-STAT3 or p-AKT.Whereas,knockdown of CXCL1 in BC cells attenuates these effects.Moreover,CXCL1 induces the expression of MMP2/9 via ERK1/2pathway.The blockage of ERK by its antagonists(U0126)can abolish the effect of CXCL1 on MMP2/9 expression.Furthermore,immunohistochemical(IHC)analysis reveals a strong positive correlation between CXCL1 and p-ERK1/2 expressions in BC tissues.Conclusion: Our study illustrates that CXCL1 is highly expressed in ER-negative BC and stimulates cell migration and invasion through ERK/MMP2/9 pathway,which may serve as a potential therapeutic target in ER-negative breast cancer.