Simple SummarySince TNBC shows the worst prognosis and limited treatment options, exploring novel molecular targets is urgently needed for effective treatment of TNBC. In this study, we demonstrated that LEMD1 is highly expressed in TNBC and contributes to poor prognosis of TNBC patients. LEMD1 silencing not only inhibited the proliferation and migration of TNBC cells in vitro, but also abolished tumor formation of TNBC cells in vivo. Mechanistically, LEMD1 promotes the progress of TNBC by activating the ERK signaling pathway. Knockdown of LEMD1 renders TNBC cells more sensitive to paclitaxel. Our results uncovered LEMD1 as a novel oncogene in TNBC, and targeting LEMD1 might be a promising therapeutic approach for the effective treatment of TNBC patients.AbstractBreast cancer is the most common deadly malignancy in women worldwide. In particular, triple-negative breast cancer (TNBC) exhibits the worst prognosis among four subtypes of breast cancer due to limited treatment options. Exploring novel therapeutic targets holds promise for developing effective treatments for TNBC. Here, we demonstrated for the first time that LEMD1 (LEM domain containing 1) is highly expressed in TNBC and contributes to reduced survival in TNBC patients, through analysis of both bioinformatic databases and collected patient samples. Furthermore, LEMD1 silencing not only inhibited the proliferation and migration of TNBC cells in vitro, but also abolished tumor formation of TNBC cells in vivo. Knockdown of LEMD1 enhanced the sensitivity of TNBC cells to paclitaxel. Mechanistically, LEMD1 promoted the progress of TNBC by activating the ERK signaling pathway. In summary, our study revealed that LEMD1 may act as a novel oncogene in TNBC, and targeting LEMD1 may be exploited as a promising therapeutic approach to enhance the efficacy of chemotherapy against TNBC.