Activated glucocorticoid receptor is an estrogen receptor silencer in ER+ metastatic breast cancer
Madhuri Manivannan1,2, Charly Jehanno1,2, Michal Kloc1,2,3
1Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
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.
Insights
Glucocorticoid receptor activation with dexamethasone reduces estrogen receptor (ER) levels and liver metastases in ER-positive breast cancer models. This suggests dexamethasone may treat patients with endocrine-resistant ER+ metastatic breast cancer, especially those with ESR1 mutations.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Estrogen Receptor alpha (ER)-positive, HER2-negative breast cancers typically respond to endocrine therapy but can develop resistance.
- Mutations in ESR1 are a common cause of endocrine resistance in metastatic ER+ breast cancer, leading to poor patient outcomes.
- Developing therapies to overcome endocrine resistance in metastatic breast cancer is a critical unmet need.
Purpose of the Study:
- To investigate the therapeutic potential of glucocorticoid receptor (GR) activation in ER+ metastatic breast cancer, particularly in the context of ESR1 mutations.
- To elucidate the molecular mechanisms by which GR activation impacts ER-positive breast cancer growth and ER signaling.
Main Methods:
- Utilized mouse models bearing ESR1 mutant metastases.
- Administered dexamethasone to activate the GR pathway.
- Performed transcriptomic and proteomic profiling to analyze molecular changes.
- Conducted Chromatin Immunoprecipitation sequencing (ChIP-Seq) to assess ER and GR binding to chromatin.
- Analyzed GR activity signatures in patient data.
Main Results:
- GR activation by dexamethasone significantly decreased liver metastases and prolonged survival in mice with ESR1 mutant breast cancer.
- GR activation led to a downregulation of the estrogen response signature and a substantial reduction in ER protein levels.
- Prolonged dexamethasone treatment resulted in near-complete abrogation of ER chromatin binding, with GR binding to a subset of ER-related genes, including ESR1.
- A GR activity signature was found to predict favorable clinical outcomes in patients with ER+ breast cancer.
Conclusions:
- Dexamethasone inhibits ER+ metastatic breast cancer growth by inducing ER depletion and abrogating ER chromatin binding.
- GR activation represents a potential therapeutic strategy for ER+ metastatic breast cancer, especially for patients with refractory ESR1 mutations.
- The findings support the clinical investigation of dexamethasone for treating patients with advanced ER+ breast cancer, including those with endocrine resistance.
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