EIF4EBP1 in Breast Cancer: Translational Control, Regulatory Networks, and Therapeutic Frontiers.

Abstract

Eukaryotic initiation factor 4E-binding protein 1 (EIF4EBP1/4E-BP1) is a pivotal translational regulator with context-dependent roles in breast cancer pathogenesis. Its phosphorylation status, dynamically controlled by mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, dictates a dualistic function: hypophosphorylated EIF4EBP1 suppresses oncogenesis by sequestering eIF4E and inhibiting cap-dependent translation of pro-tumorigenic mRNAs (e.g., cyclin D1 and c-MYC), while hyperphosphorylation promotes tumor progression and therapeutic resistance. EIF4EBP1 amplification (8p11-p12) is correlated with endocrine resistance and poor prognosis. EIF4EBP1 modulates cell cycle checkpoints, metabolic adaptation under stress, and resistance to cyclin-dependent kinase (CDK) 4 and 6 inhibitors and rapalogs via feedback loops (e.g., SGK3/Akt reactivation). Emerging therapeutic strategies, such as ATP-competitive mTOR inhibitors, bisteric compounds, and agents targeting polyamine metabolism or upstream kinases, exploit the dynamics of EIF4EBP1 phosphorylation. As a biomarker, phosphorylated EIF4EBP1 levels predict tumor aggressiveness and treatment failure, positioning it as a critical node for precision oncology. Future research must address spatial heterogeneity and leverage multi-omics/AI-driven approaches.