/ News, Research
New study reveals glucocorticoid receptor activation suppresses estrogen receptor signaling and reduces metastatic burden (Bentires-Alj Lab)
A research team from our department has uncovered a surprising therapeutic potential of the commonly used synthetic glucocorticoid dexamethasone in advanced Estrogen Receptor–positive (ER+), HER2-negative breast cancer. The findings, published today in EMBO Molecular Medicine, reveal that activating the Glucocorticoid Receptor (GR) reduces liver metastases and prolongs overall survival in preclinical models of endocrine therapy-resistant disease—particularly in metastases bearing ESR1 mutations.
ER+ breast cancers typically respond well to endocrine therapy, yet up to 55% of patients acquire ESR1 mutations with a metastatic relapse that leave standard treatments, including aromatase inhibitors and Selective Estrogen Receptor Degraders (SERDs), far less effective. These resistant tumors frequently spread to the liver, where treatment options remain limited. In this study, the Bentires-Alj Lab used metastatic in vivo and ex vivo models harboring the common ESR1mutations D538G and Y537S. They found that dexamethasone-mediated GR activation not only reduced the viability of ER+ cancer cells but also decreased liver metastatic burden and extended overall survival in mice. Mechanistic analyses revealed a striking phenomenon: upon GR activation, estrogen response genes were silenced, and ERα itself was depleted at both mRNA and protein levels.
Integrative transcriptomic, proteomic, and chromatin-binding analyses demonstrated that prolonged dexamethasone exposure nearly eliminated genome-wide ER chromatin binding.GR bound to key ER-regulated regions—including those controlling ESR1—effectively shutting down estrogen-driven transcriptional programs essential for cancer cell growth. This ER-silencing effect was also observed in patient-derived tumor organoids. Importantly, a GR activity signature derived from the study predicted improved outcomes in patients with ER+ breast cancer in the METABRIC cohort and strongly anti-correlated with ESR1 expression, suggesting a clinically meaningful link between GR activation and reduced ER signaling.
The researchers around first author Madhuri Manivannan also compared dexamethasone with current therapies. In ESR1mutant resistant models, dexamethasone outperformed the commonly used SERD, Fulvestrant, in reducing liver metastatic outgrowth, and acted synergistically with CDK4/6 inhibitors—standard first-line treatments in ER+ metastatic breast cancer.
Collectively, these findings identify dexamethasone as a potential estrogen receptor silencer with a distinct mechanism of action and highlight the possibility of repurposing for patients with advanced ER+ breast cancer, especially those with ESR1-mutant, treatment-refractory metastatic disease. The study offers a promising new direction in addressing one of the most critical unmet needs in breast cancer therapy.
Congratulations to everybody involved.
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