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  • Interferon-Related Hub Genes in Resistant Breast Cancer CAFs

  • Zahra Sadat Tabatabaei,1 Fatemeh Kazemzadeh,2 Razieh Heidari,3 Seyed Abbas Mirzaei,4,*
    1. Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
    2. Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
    3. Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran.
    4. Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.


  • Introduction: Cancer-associated fibroblasts (CAFs) are important components of the breast cancer tumor microenvironment and exhibit substantial molecular and functional heterogeneity. Distinct CAF phenotypes may influence tumor progression, cellular communication, immune regulation, and responses to anticancer treatment. Previous studies have suggested that interferon-related transcriptional programs may occur in specific CAF populations; however, the molecular characteristics of CAFs associated with a resistant phenotype remain incompletely understood. This study aimed to identify differentially expressed genes and key hub genes associated with the molecular phenotype of resistant breast cancer-associated fibroblasts and to explore their potential biological relevance.
  • Methods: The publicly available gene-expression dataset GSE108565 was obtained from the Gene Expression Omnibus (GEO) database. The dataset comprised 14 breast cancer-associated fibroblast samples, including seven sensitive CAF samples (S1–S7) and seven resistant CAF samples (R1–R7). Gene-expression data were preprocessed and normalized to reduce technical variation and improve comparability among samples. The distribution of expression values before and after normalization was evaluated to assess data quality and sample consistency (Figure 1). Differential expression analysis between resistant and sensitive CAFs was subsequently performed using the limma package in R. The identified differentially expressed genes (DEGs) were visualized using a volcano plot (Figure 2). Approximately 600 DEGs were identified. To investigate potential molecular interactions among these genes, a protein–protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape (Figure 3,4). The cytoHubba plugin was then applied using the Maximal Clique Centrality (MCC) algorithm to identify highly connected hub genes.
  • Results: MCC-based network analysis identified 10 prominent hub genes: OAS2, DDX58, MX1, ISG15, IFIT2, OAS1, IFIT3, OASL, OAS3, and RSAD2. Notably, all 10 hub genes showed increased expression in resistant CAFs compared with sensitive CAFs. Their expression patterns were further examined across individual samples, demonstrating coordinated upregulation in the resistant group (Figure 4). This consistent pattern may indicate that the identified genes represent a coordinated molecular program rather than independent alterations in individual genes. Functional interpretation suggested strong associations with type I interferon signaling, interferon-stimulated gene activity, innate immune responses, antiviral defense, and intracellular nucleic-acid sensing. The simultaneous upregulation of OAS-family genes together with MX1, ISG15, IFIT2, IFIT3, DDX58, OASL, and RSAD2 may reflect activation of an interferon-associated state in resistant CAFs.
  • Conclusion: The present transcriptomic and PPI-network analysis identified a coherent interferon-related hub gene signature in resistant breast cancer-associated fibroblasts. The coordinated upregulation of OAS2, DDX58, MX1, ISG15, IFIT2, OAS1, IFIT3, OASL, OAS3, and RSAD2 may indicate enhanced interferon-associated innate immune activity in the resistant CAF phenotype. This molecular state could potentially contribute to resistance through altered stromal signaling, CAF–tumor cell communication, immune modulation, and cellular stress adaptation. However, these mechanisms should be considered potential explanations rather than established causal mechanisms. Functional studies will therefore be required to determine whether and how these hub genes contribute to the resistant phenotype. These findings may guide future mechanistic and functional validation studies. The identified genes may represent candidate biomarkers for further characterization and experimental investigation of resistant CAFs.
  • Keywords: Cancer-associated fibroblasts; Breast cancer; Drug resistance; Interferon signaling; Hub genes

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