Similar Datasets
Project description:Estrogen Receptor alpha (ERα)-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 ERα 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.
2025-10-15 | GSE286891 | GEO
Project description:Estrogen Receptor alpha (ERα)-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 ERα 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.
2025-10-15 | GSE286890 | GEO
Project description:Activated Glucocorticoid Receptor is an Estrogen Receptor Silencer in ERα+ metastatic breast cancer.
| PRJNA1210499 | ENA
Project description:Activated Glucocorticoid Receptor is an Estrogen Receptor Silencer in ERα+ metastatic breast cancer [ChIP-seq]
| PRJNA1210504 | ENA
Project description:Activated Glucocorticoid Receptor is an Estrogen Receptor Silencer in ERα+ metastatic breast cancer [RNA-seq]
| PRJNA1210501 | ENA
Project description:Receptor levels are a key mechanism by which cells regulate their response to stimuli. The levels of estrogen receptor-α (ERα) impact breast cancer cell proliferation and are used to predict prognosis and sensitivity to endocrine therapy. Despite the clinical application of this information, it remains unclear how different cellular processes interact as a system to control ERα levels. To address this question, experimental results from the ERα-positive human breast cancer cell line (MCF-7) treated with 17-β-estradiol or vehicle control were used to develop a mass-action kinetic model of ERα regulation. Model analysis determined that RNA dynamics could be captured through phosphorylated ERα (pERα)-dependent feedback on transcription. Experimental analysis confirmed that pERα-S118 binds to the estrogen receptor-1 (ESR1) promoter, suggesting that pERα can feedback on ESR1 transcription. Protein dynamics required a separate mechanism in which the degradation rate for pERα was 8.3-fold higher than nonphosphorylated ERα. Using a model with both mechanisms, the root mean square error was 0.078. Sensitivity analysis of this combined model determined that while multiple mechanisms regulate ERα levels, pERα-dependent feedback elicited the strongest effect. Combined, our computational and experimental results identify phosphorylation of ERα as a critical decision point that coordinates the cellular circuitry to regulate ERα levels.
| S-EPMC4415015 | biostudies-literature
Project description:Estrogen receptor-positive (ER+) breast cancer seriously endangers the women's physical and mental health worldwide and ER targeting therapy is vital. Here, we found that a citrus polymethoxyflavones (PMFs)-rich hydrolysate (C-H) and its major components (nobiletin and 3-methoxynobiletin) potently degrade ERα protein via the ubiquitin-proteasome pathway, thereby impairing the proliferation of ER+ breast cancer cells. Moreover, our study exhibited that C-H combined with tamoxifen (TAM) inhibited the cell proliferation of ER+ breast cancer in vitro. It was further confirmed that C-H decreased tumor growth of ER+ breast cancer in tumor-bearing 129 mice in vivo and improved the efficacy of tamoxifen. Our study revealed that the citrus PMFs have potential applications as pharmaceutical and healthcare products in breast cancer treatment by targeting ERα protein degradation.
| S-EPMC11252954 | biostudies-literature
Project description:Tumor mutations in the gene encoding estrogen receptor alpha (ESR1) have been identified in metastatic breast cancer patients with endocrine therapy resistance. However, relatively little is known about the occurrence of mutations in the progesterone receptor (PGR) gene in this population. The study objective was to determine the frequency and prognostic significance of tumor PGR mutations for patients with estrogen receptor (ER)-positive metastatic breast cancer. Thirty-five women with metastatic or locally recurrent ER+ breast cancer were included in this IRB-approved, retrospective study. Targeted next-generation sequencing of the PGR gene was performed on isolated tumor DNA. Associations between mutation status and clinicopathologic factors were analyzed as well as overall survival (OS) from time of metastatic diagnosis. The effect of the PGR variant Y890C (c.2669A>G) identified in this cohort on PR transactivation function was tested using ER-PR- (MDA-MB-231), ER+PR+ (T47D), and ER+PR- (T47D PR KO) breast cancer cell lines. There were 71 occurrences of protein-coding PGR variants in 67% (24/36; 95% CI 49-81%) of lesions. Of the 49 unique variants, 14 are single nucleotide polymorphisms (SNPs). Excluding SNPs, the median OS of patients with PGR variants was 32 months compared to 79 months with wild-type PGR (p = 0.42). The most frequently occurring (4/36 lesions) non-SNP variant was Y890C. Cells expressing Y890C had reduced progestin-stimulated PR transactivation compared to cells expressing wild-type PR. PGR variants occur frequently in ER+ metastatic breast cancer. Although some variants are SNPs, others are predicted to be functionally deleterious as demonstrated with Y890C PR.
| S-EPMC7152560 | biostudies-literature
Project description:Estrogen receptor-positive (ER+) breast cancer is not considered immunogenic and, to date, has been proven resistant to immunotherapy. Endocrine therapy remains the cornerstone of treatment for ER+ breast cancers. However, constitutively activating mutations in the estrogen receptor alpha (ESR1) gene can emerge during treatment, rendering tumors resistant to endocrine therapy. Although these mutations represent a pathway of resistance, they also represent a potential source of neoepitopes that can be targeted by immunotherapy. In this study, we investigated ESR1 mutations as novel targets for breast cancer immunotherapy. Using machine learning algorithms, we identified ESR1-derived peptides predicted to form stable complexes with HLA-A*0201. We then validated the binding affinity and stability of the top predicted peptides through in vitro binding and dissociation assays and showed that these peptides bind HLA-A*0201 with high affinity and stability. Using tetramer assays, we confirmed the presence and expansion potential of antigen-specific CTLs from healthy female donors. Finally, using in vitro cytotoxicity assays, we showed the lysis of peptide-pulsed targets and breast cancer cells expressing common ESR1 mutations by expanded antigen-specific CTLs. Ultimately, we identified five peptides derived from the three most common ESR1 mutations (D538G, Y537S, and E380Q) and their associated wild-type peptides, which were the most immunogenic. Overall, these data confirm the immunogenicity of epitopes derived from ESR1 and highlight the potential of these peptides to be targeted by novel immunotherapy strategies.SignificanceEstrogen receptor (ESR1) mutations have emerged as a key factor in endocrine therapy resistance. We identified and validated five novel, immunogenic ESR1-derived peptides that could be targeted through vaccine-based immunotherapy.
| S-EPMC10883292 | biostudies-literature
Project description:Estrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(-) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.
| S-EPMC9399095 | biostudies-literature