Abstract: Objective: The aim of this study is to investigate the effect of viral macrophage inflammatory protein II (VMIP-II) on the expression of CXCR4 in the human breast cancer and the molecular mechanism.Methods: To designed and synthesized the sequence of CXCR4 core promoter were designed and synthesized,and established fireflyluciferase reported carrier;By detecting the fireflyluciferase activity of reported gene to reflect the effect of NT21MP on CXCR4 promotor; Western blotting and qRT-PCR were used to assess the expression of the related gene and miRNAs after depletion or overexpression of CXCR4,depletion of HER-2 and transfected with miRNAs inhibitor and mimic;SRB assay was used to measure the cell viability,while PI staining and AnnexinV/PI stainning was performed to analyze the cell cycle and apoptosis.Results: NT21MP down-regulated CXCR4 and up-regulated miR-125b,miR-135a and miR-146a(P < 0.05-P < 0.01);NT21MP inhibited the activity of CXCR4 core promoter;SP1 is a transcription factors,which connected with CXCR4 core promoter frequently,miR-135a mimic down-regulated SP1(P < 0.01);overexpression of CXCR4 up-regulated HER-2(P < 0.01),while depletion of CXCR4 down-regulated HER-2(P < 0.01);miR-125b down-regelated HER-2(P < 0.01);the downexpression of HER-2 can induce the expression of miR-146a;miR-146a inhibited CXCR4(P < 0.01);compared to the blank group,miR-146a and miR-135a all can inhibit cell proliferation,arrest cell cycle and induce apoptosis.Conclusions: NT21MP down-regulated the expression of CXCR4 by inducing miR-125b,miR-135a and miR-146a,inhibited the proliferation ability of breast cancer cell,and promoted theoretical basis to NT21MP applied to breast cancer treatment.