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

PurposeBreast 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-) and its forms--transmembrane (tmTNF-) and soluble (sTNF-). Experimental DesignTNF- is crucial for activating NF-{kappa}B 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-. Through integrative multi-omics and cellular functional studies, the relationship between FRMD8, iRhom2, and ADAM17 was assessed in the context of breast cancer metastasis. ResultsOur 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-. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNF- and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNF- processing. ConclusionsThis study explores how FRMD8 influences TNF- 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.