Targeting the eIF4A RNA helicase blocks translation of the MUC1-C oncoprotein

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Aberrant MUC1 C-terminal subunit (MUC1-C) overexpression is common in breast cancers, but its regulatory mechanisms remain unclear.
• Epidermal growth factor (EGF) and heregulin (HRG) stimulation upregulate MUC1-C translation in non-malignant cells.

Purpose of the Study:

• To elucidate the signaling pathways mediating growth factor-induced MUC1-C translation.
• To investigate the role of the eIF4A RNA helicase in MUC1-C overexpression.
• To explore the functional significance of MUC1-C in promoting growth factor signaling.

Main Methods:

• Stimulation of MCF-10A cells with EGF/HRG.
• Inhibition of PI3K/AKT, MEK/ERK1/2, mTORC1/S6K1, and eIF4A RNA helicase pathways.
• Analysis of MUC1-C expression and complex formation with EGFR.
• Comparison of MUC1-C regulation in non-malignant and breast cancer cells.

Main Results:

• EGF/HRG-induced MUC1-C translation is mediated by PI3K/AKT and mTORC1/S6K1 signaling, involving decreased PDCD4.
• Inhibition of eIF4A RNA helicase activity with silvestrol and CR-1-31-B blocked MUC1-C upregulation.
• MUC1-C forms complexes with EGFR, enhancing PI3K/AKT activation and promoting growth.
• Constitutive MUC1-C overexpression in breast cancer cells is sensitive to PI3K/AKT and eIF4A inhibition.

Conclusions:

• EGF-induced MUC1-C expression relies on PI3K/AKT and eIF4A RNA helicase.
• MUC1-C overexpression promotes an autoinductive loop with EGFR signaling.
• Targeting the eIF4A RNA helicase represents a novel therapeutic strategy for MUC1-C-driven breast cancers.