AccScience Publishing / GPD / Online First / DOI: 10.36922/GPD025250050
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ORIGINAL RESEARCH ARTICLE

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

Guang Yang1* ,  Zhaorui Hao2 ,  Xingrui Liu2 ,  Zixi Tang2
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1 Hubei Provincial Demonstration Center for Experimental Medicine, School of Medicine, Jianghan University, Wuhan, Hubei, China
2 School of Medicine, Jianghan University, Wuhan, Hubei, China
GPD, 025250050 https://doi.org/10.36922/GPD025250050
Received: 21 June 2025 | Revised: 18 August 2025 | Accepted: 24 October 2025 | Published online: 14 November 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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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.

Graphical abstract
Keywords
Breast invasive carcinoma
M2-like tumor-associated macrophages
Hub genes
Mendelian randomization
Genomics of drug sensitivity
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.
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Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
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