We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) plays a crucial role in the promotion of migration of breast cancer cells. Lamellipodia and filopodia protrusions play fundamental roles, involving dynamic cytoskeleton reorganization in the metastasis of cancer. Here, we observed that the expression levels of both HBXIP and Calpain small subunit 1 (Capn4) were very high in clinical metastatic lymph nodes of breast tumor. Then, we found that HBXIP was able to up-regulate Capn4 at the levels of promoter, mRNA and protein in breast cancer cells through activation of ERK1/2. Moreover, we showed that HBXIP activated ERK1/2 through up-regulating MEKK2. In function, we revealed that HBXIP increased the filopodia formation through Capn4, resulting in cell migration. Thus, we conclude that the oncoprotein HBXIP enhances the migration of breast cancer through increasing filopodia formation involving MEKK2/ERK1/2/Capn4 signaling. Therapeutically, HBXIP may serve as a novel target in breast cancer.