Triple-negative breast cancer (TNBC) that lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is a breast cancer subtype with very aggressive metastasis and poor prognosis. Unique cartilage matrix-associated protein (UCMA) is a vitamin K-dependent protein (VKDP) with a high-density gamma-carboxyglutamic acid (Gla) domain due to the action of vitamin K. UCMA promotes osteoblast differentiation and mineral deposition in bone and suppresses calcification in vessels. However, correlation between UCMA and TNBC is unknown. This study investigated the inhibitory effect of UCMA on TNBC cell in vitro migration, invasion, and colony formation in addition to in vivo tumorigenesis. Cell migration and invasion significantly decreased in Ucma-overexpressing MDA-MB-231 and 4T1 cells compared to the mock control cells. Also, colony formation and the number of colonies significantly decreased in Ucma-overexpressing MDA-MB-231 and 4T1 cells. These results indicate that UCMA significantly inhibits the migration, invasion, and colony formation of TNBC cells. In an in vivo xenograft mouse model, tumor growth significantly decreased in mice bearing Ucma-overexpressing TNBC cells compared to the mock control cells, indicating that UCMA reduced in vivo tumor growth, similar to the inhibitory role of UCMA in vitro. Survival analysis using publicly available database showed that high UCMA expression significantly correlated with favorable relapse-free survival in TNBC patients compared to those with the other VKDPs, matrix Gla protein (MGP) and osteocalcin (OCN). Collectively, this study suggests that UCMA is a promising new therapeutic agent for TNBC. (c) 2020 Elsevier Inc. All rights reserved.