{"title":"Integrative immunogenomic and experimental characterization reveals CXCL9, CXCL13, CCL5 and CD74 as key oncogenic drivers in breast cancer.","authors":"Mohammed A Alshehri, Mohammed Alissa","doi":"10.1007/s00335-026-10218-3","DOIUrl":null,"url":null,"abstract":"<p><p>Breast cancer remains the most prevalent malignancy among women worldwide, driven by complex interactions between tumor-intrinsic factors and the immune microenvironment. Understanding immune-related molecular regulators is essential to improve diagnostic and therapeutic strategies. Transcriptomic data from the TCGA-BRCA dataset (1109 tumor and 113 normal samples) were analyzed to identify differentially expressed immune-related genes by cross-referencing ImmPort and InnateDB gene sets. Protein-protein interaction networks were constructed using STRING and Cytoscape to identify hub genes. Validation analyses were conducted using GSCA, cBioPortal, and GEO datasets. miRNA-mRNA regulatory interactions were explored using TargetScan, miRDB, miRWalk, and miRTarBase databases, followed by dual-luciferase reporter assays. Functional characterization of CCL5 and CD74 was performed through siRNA-mediated knockdown in breast cancer cell lines, proliferation, colony formation, and wound healing assays, as well as xenograft mouse models. Four key immune-related hub genes, including CXCL9, CXCL13, CCL5, and CD74 were identified as significantly upregulated in breast cancer. Epigenetic and prognostic analyses revealed that these genes were influenced by promoter methylation and correlated with poor survival outcomes. miRNA-mRNA network analysis identified hsa-miR-146a-5p and hsa-miR-200c-3p as central regulators, validated by luciferase assays. Functional studies showed that silencing CCL5 and CD74 significantly reduced cell proliferation, migration, and tumor growth in vivo, confirming their oncogenic roles. This integrative multi-omics and experimental study identified CCL5 and CD74 as key immune-oncogenic drivers of breast cancer progression. Their modulation of the MIF-CD74 signaling axis highlights potential therapeutic targets for immunomodulatory interventions and combination therapy in breast cancer.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":"37 1","pages":""},"PeriodicalIF":2.6000,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mammalian Genome","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s00335-026-10218-3","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Breast cancer remains the most prevalent malignancy among women worldwide, driven by complex interactions between tumor-intrinsic factors and the immune microenvironment. Understanding immune-related molecular regulators is essential to improve diagnostic and therapeutic strategies. Transcriptomic data from the TCGA-BRCA dataset (1109 tumor and 113 normal samples) were analyzed to identify differentially expressed immune-related genes by cross-referencing ImmPort and InnateDB gene sets. Protein-protein interaction networks were constructed using STRING and Cytoscape to identify hub genes. Validation analyses were conducted using GSCA, cBioPortal, and GEO datasets. miRNA-mRNA regulatory interactions were explored using TargetScan, miRDB, miRWalk, and miRTarBase databases, followed by dual-luciferase reporter assays. Functional characterization of CCL5 and CD74 was performed through siRNA-mediated knockdown in breast cancer cell lines, proliferation, colony formation, and wound healing assays, as well as xenograft mouse models. Four key immune-related hub genes, including CXCL9, CXCL13, CCL5, and CD74 were identified as significantly upregulated in breast cancer. Epigenetic and prognostic analyses revealed that these genes were influenced by promoter methylation and correlated with poor survival outcomes. miRNA-mRNA network analysis identified hsa-miR-146a-5p and hsa-miR-200c-3p as central regulators, validated by luciferase assays. Functional studies showed that silencing CCL5 and CD74 significantly reduced cell proliferation, migration, and tumor growth in vivo, confirming their oncogenic roles. This integrative multi-omics and experimental study identified CCL5 and CD74 as key immune-oncogenic drivers of breast cancer progression. Their modulation of the MIF-CD74 signaling axis highlights potential therapeutic targets for immunomodulatory interventions and combination therapy in breast cancer.
期刊介绍：
Mammalian Genome focuses on the experimental, theoretical and technical aspects of genetics, genomics, epigenetics and systems biology in mouse, human and other mammalian species, with an emphasis on the relationship between genotype and phenotype, elucidation of biological and disease pathways as well as experimental aspects of interventions, therapeutics, and precision medicine. The journal aims to publish high quality original papers that present novel findings in all areas of mammalian genetic research as well as review articles on areas of topical interest. The journal will also feature commentaries and editorials to inform readers of breakthrough discoveries as well as issues of research standards, policies and ethics.
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