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Peer-reviewedCC BYCell communication and signaling : CCS

Spatially resolved GR-TGFβ co-activation underlies cell-type-specific signalling in triple-negative breast cancer.

  • Henriett Butz1,2,3,4
  • Lőrinc Pongor5,6
  • Viktória Vereczki7,8
  • Csaba Dávid8
  • Kristóf Szakács9
  • Viktória Kovács10
  • Szonja Polett Pósa7
  • Laura Svajda11
  • József Tóvári11
  • Anikó Bozsik7
  • Vince K Grolmusz7,12
  • Tímea Pócza7
3 more authors
  • János Papp7
  • Erika Tóth13
  • Attila Patócs7,5,14
14 affiliations
  1. 1Department of Molecular Genetics and National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary. [email protected].
  2. 2Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary. [email protected].
  3. 3HUN-REN-ONKOL-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary. [email protected].
  4. 4Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary. [email protected].
  5. 5HUN-REN-ONKOL-TTK-HCEMM Oncogenomics Research Group, Budapest, Hungary.
  6. 6MTA-HCEMM Lendület "Momentum" Cancer Genomics and Epigenetics Research Group / Cancer Genomics and Epigenetics Core Group, HCEMM, Szeged, Hungary.
  7. 7Department of Molecular Genetics and National Tumorbiology Laboratory, National Institute of Oncology, Budapest, Hungary.
  8. 8Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary.
  9. 9Department of Oncology Biobank, National Institute of Oncology, Budapest, Hungary.
  10. 10National Academy of Scientist Education, Semmelweis University, Budapest, Hungary.
  11. 11Department of Experimental Pharmacology and the National Tumoriology Laboratory, National Institute of Oncology, Budapest, Hungary.
  12. 12Lendület "Momentum" Hereditary Cancers Systems Biology Research Group, Hungarian Academy of Sciences - National Institute of Oncology, Budapest, Hungary.
  13. 13Department of Surgical and Molecular Pathology, National Institute of Oncology, Budapest, Hungary.
  14. 14Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary.
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Abstract

Background

The 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

We 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

GR 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

These 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.

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Cite

BibTeXRIS
BibTeX
@article{butz2026spatially,
  title = {{Spatially resolved GR-TGFβ co-activation underlies cell-type-specific signalling in triple-negative breast cancer.}},
  author = {Henriett Butz and Lőrinc Pongor and Viktória Vereczki and Csaba Dávid and Kristóf Szakács and Viktória Kovács and Szonja Polett Pósa and Laura Svajda and József Tóvári and Anikó Bozsik and Vince K Grolmusz and Tímea Pócza and János Papp and Erika Tóth and Attila Patócs},
  journal = {Cell communication and signaling : CCS},
  year = {2026},
  month = jul,
  doi = {10.1186/s12964-026-03104-7},
  url = {https://europepmc.org/article/MED/42972597},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Spatially resolved GR-TGFβ co-activation underlies cell-type-specific signalling in triple-negative breast cancer.
AU  - Henriett Butz
AU  - Lőrinc Pongor
AU  - Viktória Vereczki
AU  - Csaba Dávid
AU  - Kristóf Szakács
AU  - Viktória Kovács
AU  - Szonja Polett Pósa
AU  - Laura Svajda
AU  - József Tóvári
AU  - Anikó Bozsik
AU  - Vince K Grolmusz
AU  - Tímea Pócza
AU  - János Papp
AU  - Erika Tóth
AU  - Attila Patócs
PY  - 2026
DA  - 2026/07/28
JO  - Cell communication and signaling : CCS
DO  - 10.1186/s12964-026-03104-7
UR  - https://europepmc.org/article/MED/42972597
AB  - Background  The 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  We 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  GR 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  These 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.
SN  - 1478-811X
ER  -