{
  "abstract": "Background\n\nThe clinical relevance of glucocorticoid receptor (GR) activation in triple-negative breast cancer (TNBC) remains controversial. While preclinical studies link GR activity to tumour progression, clinical data are inconsistent, despite the routine use of synthetic glucocorticoids as supportive therapy during chemotherapy. This paradox suggests that GR signalling may be highly context- and cell-type-specific within the tumour microenvironment. Understanding the spatial organisation and molecular partners of glucocorticoid receptor signalling is therefore essential to clarify its functional and clinical impact.Methods\n\nWe comprehensively characterised spatially resolved GR expression and signalling across malignant, stromal, and immune compartments in human triple-negative breast cancer specimens. GR protein expression was assessed by immunohistochemistry, while spatial transcriptomics was used to resolve compartment-specific transcriptional programs. Stereological confocal microscopy enabled quantitative analysis of GR and transforming growth factor beta receptor 2 (TGFBR2) co-expression at single-cell resolution in a spatial distribution. These spatial data were integrated with bulk and single-cell RNA sequencing datasets to define signalling states, ligand dependence, and pathway interactions. Intercellular communication analyses were applied to identify signalling at tumour-immune interfaces. Functional relevance was assessed using in vitro migration assays and transcriptome sequencing following glucocorticoid stimulation with or without TGFBR2 inhibition. Associations with clinical outcome were evaluated using survival analyses of pathway-correlated gene signatures.Results\n\nGR expression was enriched within the tumour microenvironment and associated with shared gene programs across tumour and stromal populations, prominently involving TGFβ pathway components. Stereological protein analyses revealed increased GR activation at invasive tumour edges and adjacent normal epithelium, accompanied by marked co-localisation with TGFBR2. Spatial transcriptomics demonstrated predominantly ligand-independent GR activation in tumour cells, whereas tumour-infiltrating immune cells displayed ligand-dependent signalling linked to local corticosteroid metabolism. Intercellular communication analyses identified enhanced GR-TGFβ signalling at the tumour-immune interface. Functionally, glucocorticoid-induced tumour cell migration was abolished by TGFBR2 inhibition. Clinically, GR-correlated and glucocorticoid-induced TGFβ gene signatures were associated with reduced overall survival.Conclusions\n\nThese findings reveal spatially regulated, cell-type-specific GR-TGFβ co-activation in TNBC. This signalling axis underlies pro-migratory tumour behaviour and adverse clinical outcome, identifying a potential prognostic marker and therapeutic vulnerability with important implications for glucocorticoid use in cancer treatment.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Molecular Genetics and National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary. butz.henriett@oncol.hu.",
    "Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary. butz.henriett@oncol.hu.",
    "HUN-REN-ONKOL-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary. butz.henriett@oncol.hu.",
    "Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary. butz.henriett@oncol.hu.",
    "HUN-REN-ONKOL-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary.",
    "MTA-HCEMM Lendület \"Momentum\" Cancer Genomics and Epigenetics Research Group / Cancer Genomics and Epigenetics Core Group, HCEMM, Szeged, Hungary.",
    "Department of Molecular Genetics and National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary.",
    "Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.",
    "Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.",
    "National Academy of Scientist Education, Semmelweis University, Budapest, Hungary.",
    "Department of Experimental Pharmacology and the National Tumoriology Laboratory, National Institute of Oncology, Budapest, Hungary.",
    "Lendület \"Momentum\" Hereditary Cancers Systems Biology Research Group, Hungarian Academy of Sciences - National Institute of Oncology, Budapest, Hungary.",
    "Department of Surgical and Molecular Pathology, National Institute of Oncology, Budapest, Hungary.",
    "Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Henriett Butz"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Lőrinc Pongor"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Viktória Vereczki"
    },
    {
      "affs": [
        7
      ],
      "name": "Csaba Dávid"
    },
    {
      "affs": [
        8
      ],
      "name": "Kristóf Szakács"
    },
    {
      "affs": [
        9
      ],
      "name": "Viktória Kovács"
    },
    {
      "affs": [
        6
      ],
      "name": "Szonja Polett Pósa"
    },
    {
      "affs": [
        10
      ],
      "name": "Laura Svajda"
    },
    {
      "affs": [
        10
      ],
      "name": "József Tóvári"
    },
    {
      "affs": [
        6
      ],
      "name": "Anikó Bozsik"
    },
    {
      "affs": [
        6,
        11
      ],
      "name": "Vince K Grolmusz"
    },
    {
      "affs": [
        6
      ],
      "name": "Tímea Pócza"
    },
    {
      "affs": [
        6
      ],
      "name": "János Papp"
    },
    {
      "affs": [
        12
      ],
      "name": "Erika Tóth"
    },
    {
      "affs": [
        6,
        4,
        13
      ],
      "name": "Attila Patócs"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4ta885k1ng8ze.bib",
  "cited_by": 0,
  "doi": "10.1186/s12964-026-03104-7",
  "fulltext_url": "https://europepmc.org/articles/PMC13729666",
  "id": "4ta885k1ng8ze",
  "issns": [
    "1478-811X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42972597",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "1306|Breast Cancer Treatment Studies"
    ]
  ],
  "openalex": "W7171513988",
  "pdf_url": "https://europepmc.org/articles/PMC13729666?pdf=render",
  "pmcid": "PMC13729666",
  "pmid": "42972597",
  "published": "2026-07-28",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/4ta885k1ng8ze.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:45Z",
      "native_id": "MED:42972597",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42972597"
    },
    {
      "first_seen": "2026-11-07T12:22:22Z",
      "native_id": "PMC13729666",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s12964-026-03104-7"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Breast Cancer Treatment Studies",
      "subfield": "oncology"
    }
  ],
  "title": "Spatially resolved GR-TGFβ co-activation underlies cell-type-specific signalling in triple-negative breast cancer.",
  "title_text": "Spatially resolved GR-TGFβ co-activation underlies cell-type-specific signalling in triple-negative breast cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:22Z",
  "url": "https://research.draconitic.com/paper/4ta885k1ng8ze",
  "venue": "Cell communication and signaling : CCS",
  "versions": []
}