Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can specifically induceapoptosis limited to various cancer cells, so this reagent is considered a promising medicine for cancer therapy.TRAIL also exerts effects on non-apoptotic signals, relevant to processes such as metastasis, autophagy andproliferation in cancer cells. However, the mechanisms of TRAIL-regulated non-apoptotic signals are unclear.The purpose of this study was to investigate MADD/CXCR7 effects in TRAIL-mediated breast cancer cellmigration. Materials and Methods: The ability of MADD/CXCR7 to regulate MVP signaling in TRAIL-mediatedbreast cancer cells migration was evaluated by transwell migration assay, quantitative RT-PCR, Westernblotting and knock down experiments. Results: In this study, we found that treatment with TRAIL resultedin induced expression levels of MADD and CXCR7 in breast cancer cells. Knock down of MADD followed bytreatment with TRAIL resulted in increased cell migration compared to either treatment alone. Similarly, throughoverexpression and knockdown experiments, we demonstrated that CXCR7 also positively regulated TRAILinhibitedmigration. Surprisingly, knock down of MADD lead to inhibition of TRAIL-induced CXCR7 mRNAand protein expression and overexpression of CXCR7 lead to the reduction of MADD expression, indicatingthat MADD is an upstream regulatory factor of TRAIL-triggered CXCR7 production and a negative feedbackmechanism between MADD and CXCR7. Furthermore, we showed that CXCR7 is involved in MADD-inhibitedmigration in breast cancer cells. Conclusions: Our work deﬁned a novel signaling pathway implicated in thecontrol of breast cancer migration.