BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype of invasive breast cancer that tests negative for PR, ER and excess HER2 protein. TNBC has a greater progression potential with poorer prognosis, compared with other types of breast cancer. Endothelial cell-specific molecule 1 (ESM1), also known as endocan, is overexpressed in various cancers including breast cancer and may play an important role in cancer progression. METHODS: The online resource of The Cancer Genome Atlas (TCGA) was used for analyzing the expression alteration of in breast cancer patient tissues. We examined the changes of various malignant behaviors of TNBC cell and tumor growth after inhibiting or overexpressing ESM1 in two human TNBC cell lines, MDA-MB-468 and MDA-MB-231. When ESM1 was knocked down or overexpressed in TNBC cell, AKT and p65 phosphorylation and Cyclin D1 expression were analyzed by western blotting. The ESM1-overexpressing TNBC cell was treated with MK-2206 and BAY-117082 at various concentrations. RESULTS: Our analyses show that is overexpressed in TNBC cell lines as well as patient tissues, which is correlated to poor prognosis. Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases proliferation, migration and invasion of TNBC cell and knockdown of ESM1 inhibits TNBC tumor growth. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating an Akt-dependent NF-κB/Cyclin D1 pathway. CONCLUSIONS: Our results demonstrate that ESM1 knockdown decreases while overexpression of ESM1 increases migration, proliferation and invasion of TNBC cell and knockdown of ESM1 inhibits tumor growth of TNBC in the xenograft mouse model. Our mechanistic study further discloses that ESM1 promotes the proliferation of TNBC cell through activating the Akt-dependent NF-κB/CyclinD1 pathway. Our findings expand the knowledge about the molecular mechanisms underlying TNBC progression and provide rationale for using ESM1 as a therapeutic target or prognostic marker for TNBC.