2025/11/19 by Madhuri Manivannan, Charly Jehanno, Michal Kloc +17 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Estrogen and related hormone effects #Prostate Cancer Treatment and Research #Advanced Breast Cancer Therapies
paper · doi:10.1038/s44321-025-00342-z
openalex publication_date 2025/11/19 · openalex created_date 2025/11/19 · openalex updated_date 2026/07/23
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.