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 (TNFa) and its forms transmembrane (tmTNFa) and soluble (sTNFa). Experimental Design: TNFa; is crucial for activating NFkB 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 domai containing proteins, as a significant regulator of tmTNFa;. 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 TNFa;. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNFa; and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNFa; processing. Conclusions: This study explores how FRMD8 influences TNFa; 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.