Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels l'endophiline A2 favorise les processus invasifs et métastatiques dans les cancers du sein triplement négatifs
Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, Epidermal Growth Factor Receptor (EGFR) is frequently activated in a subset of TNBCs and represents a viable clinical target. Since the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared to normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptormediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in 3D cell invasion, and this correlated with impaired extracellular matrix (ECM) degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared to other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal-like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis. Implications: Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers.