N7-Methylguanine-Related Gene Signature Highlights EIF4E as a Novel Therapeutic Target in HER2-Negative Breast Cancer

Abstract

Globally, breast cancer remains one of the most prevalent malignancies and a leading cause of cancer-related death in women, with over 2.3 million new cases reported annually. Despite treatment advances, one breast cancer type in particular, HER2-negative breast cancer, lacks precise therapeutic targets. Given the role of N7-methylguanosine (m7G) in gene regulation and its links to cancer progression, we investigated m7G regulatory gene expression and prognostic potential in HER2-negative breast cancer. We analysed publicly available breast cancer datasets (The Cancer Genome Atlas and the Gene Expression Omnibus (GEO)) to analyse the differential expression of 14 m7G-regulatory genes. Clustering analysis, based on m7G patterns, categorised HER2-negative patients into two subgroups. A prognostic model was established through LASSO and Cox regression; subsequently validated by survival analysis, and further supported by functional assays confirming gene function. Our model identified CCNB1 and EIF4E as high-risk genes, with EIF4E overexpression enhancing cell proliferation, migration and invasion. RNA-sequencing (RNA-seq) and pathway analyses showed that upregulated EIF4E activated Wnt signalling and extracellular matrix (ECM) components, processes required for tumour progression. High-risk patients showed reduced immune cell infiltration and poorer survival outcomes. We highlight m7G regulatory gene potential, particularly EIF4E, as prognostic markers and therapeutic targets for HER2-negative breast cancer. Targeting EIF4E-related pathways could provide new therapeutic strategies to improve breast cancer patient outcomes.