The translation factor eIF4E is a key mediator of doxorubicin resistance: insights from a triple-negative breast cancer model

Triple-negative breast cancer (TNBC) tumors are highly aggressive and typically associated with poor prognosis due to limited therapeutic options and significant chemoresistance. This study investigated the role of the translation initiation factor eIF4E in doxorubicin (Dox) resistance using a novel TNBC model. A doxorubicin-resistant cell variant, MDA_R (IC₅₀ = 1.8 µM), was derived from MDA-MB-231 cells (IC₅₀ = 0.6 µM) following prolonged exposure to Dox at its IC₂₅ concentration. Compared to the parental line, MDA_R cells exhibited enhanced migration, invasion, and drug efflux capabilities. Dox treatment sustained the phosphorylation of eIF4E at Ser209 (eIF4E-p^Ser209), which promoted activation of the VEGF pathway and secretion of matrix metalloproteinase-9 (MMP-9). This dysregulated phosphorylation correlated with increased expression of the ABCB1 drug transporter, as confirmed by treatment with the eIF4E inhibitor 4E1RCat. In silico molecular docking and dynamics simulations further demonstrated the Dox-binding affinity of ABCB1. Moreover, at higher Dox concentrations, MDA_R cells showed elevated Nrf2 activation. Conversely, eIF4E knockdown via siRNA reduced both chemoresistance and Nrf2 expression. These findings suggest that Dox resistance enhances cellular invasiveness through an eIF4E-dependent mechanism involving ABCB1 and Nrf2, both of which are overexpressed in TNBC transcriptomic datasets, highlighting their potential clinical relevance.