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Matrix-remodeling-associated protein 8 or MXRA8 is a transmembrane protein that can bind arthritogenic alpha viruses like the Chikungunya virus and provide viral entry into cells. MXRA8 can also interact with integrin β3 and thus possibly regulate cell–cell interactions and binding to the extracellular matrix. While <i>MXRA8</i> has been associated with reduced survival in patients with colorectal and renal clear cell cancers, the role of <i>MXRA8</i> in breast cancer remains largely unexplored. Therefore, the aim of this research was to determine the role of <i>MXRA8</i> in breast cancer by knocking out <i>MXRA8</i> in the human triple-negative breast cancer cell line MDA-MB-231. The loss of <i>MXRA8</i> reduced cell proliferation in vitro but had no effect on apoptosis or migration in cultured cells. However, the loss of <i>MXRA8</i> significantly delayed tumor development and reduced metastatic dissemination to the lungs in a xenograft model. RNA sequencing identified three genes, <i>ADMATS1</i>, <i>TIE1</i>, and <i>BMP2</i>, whose expression were significantly reduced in <i>MXRA8</i>-knockout tumors compared to control tumors. <i>MXRA8</i> staining of a human breast cancer tissue array revealed higher levels of <i>MXRA8</i> in primary tumors and metastases of aggressive tumor subtypes (TNBC and HER2⁺) compared to less aggressive, ER⁺ breast cancers. Our findings demonstrate for the first time that <i>MXRA8</i> regulates the progression of human TNBC possibly through influencing the interaction of tumor cells with their microenvironment.