Identification of hub genes in breast cancer through genome-wide association and functional analyses of M2-like tumor-associated macrophages

Abstract

Breast cancer remains a leading cause of cancer-related mortality among women, and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression and poor prognosis. This study investigated M2-like TAMs to identify key genes promoting breast cancer progression. Using weighted gene co-expression network analysis (WGCNA), which leveraged the opposing prognostic roles of M1/M2 macrophages, we identified 3,127 M2-associated module genes. Intersection with up-regulated differentially expressed genes from GSE42568 and the Cancer Genome Atlas Breast Invasive Carcinoma dataset yielded 85 pivotal genes. Functional enrichment analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways linked these genes to tight junctions, Rap1 signaling, and PI3K-Akt pathways. Protein-protein interaction network analysis via CytoNCA and degree algorithms prioritized four significantly up-regulated hub genes: FOXA1, AGR2, MUC1, and ERBB3. A nomogram model demonstrated their prognostic value, while receiver operator characteristic analysis confirmed its diagnostic utility in distinguishing tumor from normal tissue. Hub gene expression positively correlated with the infiltration of mast cells, M2 macrophages, CD4⁺ T cells, monocytes, B cells, and dendritic cells. Pan-cancer analysis revealed breast cancer-specific overexpression of FOXA1 and ERBB3. Mendelian randomization using fixed-effect inverse variance weighting indicated causal associations between elevated expression of FOXA1, MUC1, and ERBB3 (β>0) and increased breast cancer risk. Drug sensitivity analysis using the Genomics of Drug Sensitivity in Cancer database identified associations between lapatinib sensitivity and expression of FOXA1, ERBB3, and MUC1. This WGCNA-based approach defines FOXA1, AGR2, MUC1, and ERBB3 as M2-like TAM-related hub genes with diagnostic, prognostic, and therapeutic relevance for breast cancer, particularly in informing drug sensitivity strategies.

Keywords

Breast invasive carcinoma / M2-like tumor-associated macrophages / Hub genes / Mendelian randomization / Genomics of drug sensitivity

Acknowledgments

None.

Funding

This work was supported by the Jianghan University Student Research Program [Grant Number 2024yb142].

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: Guang Yang

Formal Analysis: Guang Yang

Methodology: Guang Yang

Project administration: Zhaorui Hao

Supervision: Guang Yang

Validation: Zhaorui Hao, Xingrui Liu, Zixi Tang

Visualization: Zhaorui Hao, Xingrui Liu, Zixi Tang

Writing - Original Draft: Guang Yang

Writing - Review & Editing: Zhaorui Hao

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data

All data were available in the TCGA database (https://portal.gdc.cancer.gov/), GEO database (https://www.ncbi.nlm.nih.gov/geo/), and GDSC database (https://www.cancerrxgene.org/). Questions regarding data can be directed to the corresponding author.

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