Suppression of triple-negative breast cancer aggressiveness by LGALS3BP via inhibition of the TNF-α–TAK1–MMP9 axis

Abstract Transforming growth factor-β-activated kinase 1 (TAK1), which is highly expressed and aberrantly activated in triple-negative breast cancer (TNBC), plays a pivotal role in metastasis and progression. This makes it a potential therapeutic target for TNBC. Previously, we reported lectin galactoside-binding soluble 3 binding protein (LGALS3BP) as a negative regulator of TAK1 signaling in the inflammatory response and inflammation-associated cancer progression. However, the role of LGALS3BP and its molecular interaction with TAK1 in TNBC remain unclear. This study aimed to investigate the function and underlying mechanism of action of LGALS3BP in TNBC progression and determine the therapeutic potential of nanoparticle-mediated delivery of LGALS3BP in TNBC. We found that LGALS3BP overexpression suppressed the overall aggressive phenotype of TNBC cells in vitro and in vivo. LGALS3BP inhibited TNF-α-mediated gene expression of matrix metalloproteinase 9 (MMP9), which encodes a protein crucial for lung metastasis in TNBC patients. Mechanistically, LGALS3BP suppressed TNF-α-mediated activation of TAK1, a key kinase linking TNF-α stimulation and MMP9 expression in TNBC. Nanoparticle-mediated delivery enabled tumor-specific targeting and inhibited TAK1 phosphorylation and MMP9 expression in tumor tissues, suppressing primary tumor growth and lung metastasis in vivo. Our findings reveal a novel role of LGALS3BP in TNBC progression and demonstrate the therapeutic potential of nanoparticle-mediated delivery of LGALS3BP in TNBC.