Regulation of tmTNF-α Processing by FRMD8 in Triple-Negative Breast Cancer Metastasis: Insights into Molecular Pathway Dynamics

Purpose Breast cancer remains the leading cause of cancer-related mortality among women worldwide, with late-stage diagnoses prevalent in China resulting in significantly lower survival rates. This study focuses on identifying genes implicated in breast cancer metastasis, highlighting the role of Tumor Necrosis Factor-alpha (TNF-α) and its forms—transmembrane (tmTNF-α) and soluble (sTNF-α). Experimental Design TNF-α is crucial for activating NF-κB pathways that regulate genes involved in cell adhesion, migration, and immune evasion, all essential for cancer metastasis. We conducted comprehensive analyses of FRMD8, a member of the FERM domain-containing proteins, as a significant regulator of tmTNF-α. Through integrative multi-omics and cellular functional studies, the relationship between FRMD8, iRhom2, and ADAM17 was assessed in the context of breast cancer metastasis. Results Our findings reveal that FRMD8 forms a complex with iRhom2 and ADAM17, enhancing the stability and sheddase activity of ADAM17, which is vital for the release of TNF-α. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNF-α and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNF-α processing. Conclusions This study explores how FRMD8 influences TNF-α processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in breast cancer patients.