Breast cancer metastasis is the second leading cause of female mortality worldwide. Because of the heterogeneity within the group, metastatic biomarkers for triple-negative breast cancer (TNBC) providing predictive and prognosis values are urgently needed. Using RNA-Seq, we analyzed the transcriptome profiles of two groups of TNBCs tumors with or without distant metastasis. Whole transcriptome sequencing identified a set of genes implicated in TNBC metastasis with major roles in cell-cell adhesion, immune-modulation, and Wnt/β-catenin pathways. We further selected the SHISA3 gene and studied its biological significance through a series of in vitro and in vivo experiments. SHISA3 is a tumor suppressor gene, involved in several types of cancer. However, little is known concerning the role of SHISA3 in TNBC. Our in vitro and in vivo studies demonstrate that overexpression of SHISA3 inhibits TNBCs cell proliferation, metastasis and colony formation, and TNBC growth in xenografts. Mechanistically, SHISA3 inhibits TNBCs development and growth via downregulation of the epithelial-mesenchymal transition. Taken together, these results identified SHISA3 as a novel tumor suppressor gene in TNBC and suggest that SHISA3 could serve as a therapeutic target for TNBC patients.