MXRA5 promotes the progression and metastasis of breast cancer via activation of the epithelial-to-mesenchymal transition pathway

Abstract

Breast cancer remains a primary cause of cancer-associated death globally, largely due to distant metastasis and therapeutic resistance. While matrix remodeling associated 5 (MXRA5) has been implicated in inflammation and fibrosis, its specific biological function and mechanistic role in breast cancer progression remain unclear. Herein, multi-omics analysis and in vitro functional assays were employed to investigate the expression pattern, clinical significance, and biological function of MXRA5 within breast cancer. We observed that MXRA5 was considerably upregulated within breast cancer tissues in comparison with normal controls at both mRNA and protein levels. Crucially, elevated MXRA5 expression exhibited a positive correlation with advanced lymph node metastasis and impaired clinical prognosis, including overall survival, disease-specific survival, and progression-free interval, particularly within the Luminal B and HER2+ subtypes. Functional validation demonstrated that MXRA5 silencing markedly repressed the abilities of BT474 and MDA-MB-361 cells to proliferate, to migrate, and to invade in vitro, and significantly reduced lung metastasis in vivo. Mechanistically, bioinformatics analysis and pharmacological rescue experiments demonstrated that MXRA5 promotes tumor aggressiveness by activating the PI3K/AKT/mTOR signaling axis, which subsequently drives the epithelial-to-mesenchymal transition (EMT) pathway, evidenced by the positive regulation of key EMT transcription factors Snail and Twist, as well as the mesenchymal marker Vimentin. Collectively, these findings identify MXRA5 as a novel oncogenic driver in breast carcinoma and reveal its potential as a valuable prognostic biomarker and therapeutic target for managing metastatic disease.