SPANXB1 drives brain metastasis in breast cancer via MMP1 regulation: potential therapeutic insights with metformin

Abstract

Abstract Cancer-testicular antigens (CTAs) have been considered as potential prognostic biomarkers and therapeutic targets due to their specific expression and roles in tumorigenesis and metastasis. Among these, the function and mechanism of SPANXB1 in breast cancer brain metastasis (BCBM) remain poorly understood. In this study, we investigated the role of SPANXB1 in BCBM. Our results demonstrated that SPANXB1 was highly expressed in brain-tropic breast cancer cells and brain metastasis samples. Functional assays revealed that SPANXB1 promoted breast cancer cell invasion, migration, vasculogenic mimicry (VM) formation, and blood-brain barrier (BBB) extravasation, thereby accelerating the process of brain metastasis. Mechanistically, SPANXB1 facilitated chromatin opening at the MMP1 promoter region via histone H3R17me2 modification and upregulated transcription factor YY1, leading to increased MMP1 expression. In vivo experiments further confirmed the role of SPANXB1 in enhancing brain metastasis. Notably, metformin effectively inhibited the expression of SPANXB1 and MMP1, thereby attenuating BCBM progression. The present study indicates the potential of SPANXB1 as a diagnostic and therapeutic target for BCBM. Additionally, our findings suggest metformin as a promising therapeutic strategy for this highly aggressive disease.