Activated Glucocorticoid Receptor is an Estrogen Receptor Silencer in ERa+ metastatic breast cancer [ChIP-seq]

Estrogen Receptor alpha (ERa)-positive, HER2-negative breast cancers are less aggressive than other subtypes and generally 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 ligand-independent ERa activation and 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, enhances chemotherapy responsiveness, and prolongs survival. Transcriptomic profiling and proteomics profiling revealed that GR activation not only downregulates estrogen reponse signature but also induces dramatic loss of ER itself, therefore uncovering an estrogen receptor silencing action of GR. ChIP-Seq analysis revealed that prolonged Dex treatment almost completely abrogates ER chromatin binding and that GR binds a subset of ER-related genes including ESR1 itself. This was accompanied by loss of H3K27 acetylation and enhancer acetylation, hence inhibiting transcription. Finally, we found that GR activation in patient-derived organoids reduces the number of ER+ cancer cells and ERa abundance, and predicts good outcome in patients with ER+ breast cancer, using publicly available data. These data imply that administration of synthetic glucocorticoids reduces ER+ cell proliferation, inhibits metastatic ability, enhances chemotherapy efficacy and hence can be beneficial for patients with ER+ metastatic breast cancer, particularly the treatment of refractory ESR1 mutant metastases. Overall design: MCF-7 ESR1 mutant D538G cells plated in 10 cm dishes (2D monolayer), and cultured for 2 days in 2.5% Charcoal stripped FCS, phenol red free DMEM medium were vehicle or Dexamethasone (700 nM) treated for 1h or 24h, in order to assess GR and ER binding to chromatin over different exposure times to Dex.