2. Academic Validation
  3. Activated glucocorticoid receptor is an estrogen receptor silencer in ER+ metastatic breast cancer

Activated glucocorticoid receptor is an estrogen receptor silencer in ER+ metastatic breast cancer

  • EMBO Mol Med. 2025 Nov 19. doi: 10.1038/s44321-025-00342-z.
Madhuri Manivannan 1 2,  Charly Jehanno 1 2,  Michal Kloc 1 2 3,  Jorge Gomez Miragaya 1 2,  Maren Diepenbruck 1 2,  Katrin Volkmann 1 2,  Marie-May Coissieux 1 2,  Marta Palafox 1 2,  Adelin Rouchon 1 2,  Nicolas Kramer 1 2,  Alexander Schmidt 4,  Yannick Blum 1 2,  Baptiste Hamelin 1 2,  Helen Schuster 5,  Martin Heidinger 1 2 6,  Simone Muenst 5,  Marcus Vetter 7 8,  Christian Kurzeder 9,  Walter P Weber 2 6,  Mohamed Bentires-Alj 10 11
Affiliations

Affiliations

  • 1 Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
  • 2 Department of Surgery, University Hospital Basel, Basel, Switzerland.
  • 3 Swiss Institute of Bioinformatics, Basel, Switzerland.
  • 4 Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
  • 5 Institute of Pathology and Medical Genetics, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 6 Breast Center, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 7 Cancer Centre Baselland, Medical University Clinic, Cantonal Hospital Baselland, Liestal, Switzerland.
  • 8 Medical Faculty, University of Basel, Basel, Switzerland.
  • 9 Department of Gynecology, University Hospital Basel, University of Basel, Basel, Switzerland.
  • 10 Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland. [email protected].
  • 11 Department of Surgery, University Hospital Basel, Basel, Switzerland. [email protected].
PMID: 41261233 DOI: 10.1038/s44321-025-00342-z
Abstract

Estrogen receptor alpha (ER)-positive, HER2-negative breast cancers are less aggressive than Other subtypes and show good patient clinical outcome because they are likely to respond to endocrine therapies. Unfortunately, therapy-resistant metastases may develop and start an inexorable downhill course. ESR1 mutations leading to resistance to endocrine therapy are prevalent in 20-55% of patients with ER+ metastatic breast Cancer. Here, we found that Glucocorticoid Receptor (GR) activation by dexamethasone in ESR1 mutant metastases-bearing mice decreases liver metastases and prolongs survival. Transcriptomic and proteomic profiling revealed that GR activation not only downregulates estrogen response signature but also induces dramatic loss of ER itself. ChIP-Seq analyses show that prolonged dexamethasone treatment almost completely abrogates ER chromatin binding and that GR binds a subset of ER-related genes, including ESR1. Finally, the GR activity signature predicts a good outcome in patients with ER+ breast Cancer. In summary, we show that dexamethasone inhibits ER+ metastatic growth by depleting ER, and hence could be tested for treating patients with ER+ metastatic breast Cancer, particularly those suffering from refractory ESR1 mutant metastases.

Keywords

Breast Cancer; ER; GR; Metastasis; Steroid Nuclear Receptors.

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