IFITM3 promotes triple-negative breast cancer progression by regulating β-catenin localization.
TL;DR
Findings identify IFITM3 as a regulator of β-catenin localization and Wnt signaling that promotes epithelial-mesenchymal transition (EMT) and stem-like properties in TNBC cells.
Abstract
Interferon-induced transmembrane protein 3 (IFITM3) is best known as an antiviral protein, but accumulating evidence supports pro-tumorigenic functions across several cancers. Here, we examined IFITM3 in triple-negative breast cancer (TNBC). IFITM3 depletion suppressed MDA-MB-231 cell proliferation, migration, sphere formation, and xenograft tumor growth, whereas IFITM3 overexpression enhanced these phenotypes. IFITM3 depletion restored E-cadherin expression and increased membrane-associated E-cadherin-β-catenin complexes. These changes were accompanied by reduced nuclear active β-catenin and decreased Wnt/β-catenin transcriptional activity in cultured cells. Altered β-catenin localization was also observed in xenograft tumors. Conversely, IFITM3 overexpression enhanced WNT3a-responsive transcription and nuclear accumulation of active β-catenin. IFITM3 expression was elevated in breast tumors and was associated with shorter overall survival in a selected lymph-node-negative TNBC cohort. Together, these findings identify IFITM3 as a regulator of β-catenin localization and Wnt signaling that promotes epithelial-mesenchymal transition (EMT) and stem-like properties in TNBC cells.