Evaluating ER-alpha and PR interactions with chromatin in Esr1-wildtype and mutant mammary luminal cells
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ABSTRACT:
PROVIDER: PRJNA773929 | ENA |
REPOSITORIES: ENA
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Project description:To understand the interactions between ER-alpha and PR interactions with chromatin in Esr1-wildtype versus mutant mammary cells, ChIP-seq was performed against both transcription factors. Animals were treated for four days with E2 and P4, then harvested for analysis.
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Project description:To examine the effects of hormone stimulation on Esr1-wildtype and Esr1-mutant mammary glands, we will ovariectomize both wildtype and ER-mutant mice. Following ovariectomy (OVX), animals will be implanted with hormone pellets (either placebo, estrogen, and/or progesterone). Then, we perform RNA-seq on FACS-sorted mature luminal cells (ML) from mammary glands of treated mice. This analysis will allow for separation of ER mutant-intrinsic effects on gene expression vs. combinatorial effects from exposure to either estrogen or progesterone.
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Project description:Evaluating hormone responses in Esr1-wildtype and mutant mammary luminal cells [RNA-seq]
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Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript. We tested SET ER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.485, 95% CI 0.265 to 0.889, p = 0.019; OS: HR 0.314, 95% CI 0.155 to 0.637, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124647 | GEO
Project description:There is clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SETER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors (ESR1 and PGR) and robust to pre-analytical and analytical influences. We tested SETER/PR index in biopsies of metastastic HR+/HER2- breast cancer against the treatment outcomes in 140 patients. Then we customized the SETER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SETER/PR index in metastatic samples predicted longer progression-free (PFS) and overall survival (OS) when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1% to 98% of ESR1 transcripts (all had high SETER/PR index). A signature based on probe sets with good pre-analytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SETER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2- breast cancer, especially in the absence of mutated ESR1 transcript.
2019-05-30 | GSE124648 | GEO
Project description:Steroid 5α reductase 2 (SRD5A2) is crucial for prostatic development, converting testosterone to dihydrotestosterone (DHT). While 5α reductase inhibitors (5ARI) effectively reduce prostate size in benign prostate hyperplasia (BPH), their limited efficacy against BPH-related lower urinary tract symptoms (LUTS) and mechanisms of 5ARI resistance remain unclear. Here, we developed a Srd5a2-/- mouse model and employed single-cell RNA sequencing (scRNA-seq) to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial (LE) populations were observed, alongside increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)+ Luminal Epithelia 2 (LE2) cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting alternative pathways for prostate growth without SRD5A2. Human prostate biopsy analysis revealed an inverse correlation between SRD5A2 expression and LE2 markers (ESR1 and PKCα). These findings provide insights into prostate biology, 5ARI resistance mechanisms, and potential targeted therapies for BPH-related LUTS.
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Project description:The goal of this study is to analyse whether ER-/PR+ breast tumors could be transcriptionally different from ER+/PR+ and/or from triple negative breast tumors
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Project description:Samples from hormone-receptor positive breast cancer to identify transcripts related to ESR1 and PGR expression.
2019-05-30 | GSE129551 | GEO
Project description:Many Luminal breast cancers are heterogeneous, containing substantial numbers of estrogen (ER-) and progesterone (PR-) receptor-negative cells among the ER+PR+ ones. Currently, the Basal-like ER-PR- Luminobasal subpopulation in Luminal disease is not targeted for treatment. To address the relationships between ER+PR+ and ER-PR- cells in Luminal cancers and tightly control their ratios, we have generated isogenic pure Luminal (pLUM) and pure Luminobasal (pLB) cells from the same parental Luminal human breast cancer cell line. We show that pLUM suppress proliferation of pLB cells in mixed-cell 3D colonies in vitro and in pLUM:pLB mixed-cell xenografts in mice. High-throughput screening of FDA-approved oncology drugs reveal pLB cells are sensitive to the EGFR inhibitors Gefitinib and Erlotinib. In mixed-cell 3D colonies and mixed-cell solid mouse tumors, combination therapy with the antiestrogen Fulvestrant and the EGFRi Gefitinib constitutes a robust treatment strategy. We propose that response to combination endocrine/EGFRi therapies in heterogeneous Luminal cancers will improve long-term survival in patients whose primary tumors have been preselected for the appropriate biomarkers.
2014-07-14 | GSE55350 | GEO
Project description:Transcriptome analysis of ER+/PR+, ER-/PR+ and triple negative breast tumors
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