Clinical associations of ESR2 (estrogen receptor beta ERβ) expression across thousands of primary breast tumors
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ABSTRACT:
PROVIDER: PRJNA834993 | ENA |
REPOSITORIES: ENA
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Project description:PURPOSE: Estrogen receptor alpha (ERα, encoded by ESR1) is a well-characterized transcription factor expressed in more than 75% of breast tumors and is the key biomarker to direct endocrine therapies. On the other hand, much less is known about estrogen receptor beta (ERβ, encoded by ESR2) and its importance in cancer. Previous studies had some disagreement, however most reports suggested a more favorable prognosis for patients with high ESR2 expression. METHODS: To add further clarity to ESR2 in breast cancer, we interrogated a large population-based cohort of primary breast tumors (n=3207) from the SCAN-B study (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096). Spearman rank correlation was used to determine correlations between expression of ESR1 and ESR2. Kruskal-Wallis non-parametric test and Wilcoxon rank sum test were used to compare and plot expression of the ESR1 and ESR2 genes in various clinical groups such as PAM50 subtype and age groups in both the SCAN-B and TCGA cohorts. Transformed ESR2 expression data was divided into tertiles, with the first tertile defined as ESR2-high, and the bottom two tertiles at ESR2-low. Mann Whitney U test and Fisher’s exact test were used to evaluate significant differences in the clinicopathological variables for the ESR2-high and ESR2-low groups. Survival analysis was performed by Kaplan-Meier and Cox regression survival analyses that included a median follow-up of 6.2 years (IQR = 2.2). RESULTS: Using RNA-seq data, we found that ESR2 is expressed at low levels overall with a slight inverse correlation to ESR1 expression (Spearman R = -0.18, p = 2.2e-16), and highest ESR2 expression in the basal- and normal-like PAM50 subtypes. ESR2-high tumors had favorable overall survival (p=0.006), particularly in subgroups receiving endocrine therapy (p=0.03) and in triple-negative breast cancer (p=0.01). These results were generally robust in multivariable analyses accounting for patient age, size, node status, and grade. Gene modules consistent with immune response were associated to ESR2-high tumors. CONCLUSIONS: Taken together, our results indicate that ESR2 is generally expressed at low levels in breast cancer but associated with improved overall survival and may be related to immune response modulation.
2022-05-09 | GSE202203 | GEO
Project description:We found by RNA seq analysis that the expression of the cyclin D1 gene, the classic target of estrogen-stimulated transcription through an AP1 response element, negatively correlated with that of ERβ/ESR2 as measured using Spearman correlation coefficient (rho = -0.45, p = 0.005). ERβ/ESR2 expression was also negatively correlated with that of ERα/ESR1 (rho = -0.35, p = 0.033). However, ERβ/ESR2 mRNA expression positively correlated with that of IGFBP4 (rho = 0.58, p < 0.001) and CXCL12 (rho = 0.54, p < 0.001). The univariate Cox proportional hazards estimate for overall survival by ESR2 expression was 0.54 (95% CI 0.06, 5.22), suggesting a positive trend that did not reach statistical significance in this numerically limited cohort .
2022-05-18 | GSE198545 | GEO
Project description:Objective: To study the role of estrogen receptor beta in follicle development and maturation and in the response to gonadotropin stimulation aiming at superovulation. Animals: Healthy wild-type and estrogen receptor beta (ERβ) knockout female mice aged 4 weeks, 7 weeks, and 6 months. analysis. Main Outcomes: Oocyte yield after superovulation, transcriptomic profiling of cumulus cells and oocytes and immunohistochemical analyses. Results: Superovulation of ERβ knockout (Esr2-KO) mice results in reduced oocyte yield at 6-months of age compared to wild-type (WT) mice. RNA-seq analysis of cumulus cells from superovulated WT and Esr2-KO mice identified genes and pathways associated with among others adhesion, proliferation, Wnt-signaling, and placed ERβ in bipotential granulosa cell cluster. Loss of ERβ increased expression of the other estrogen receptors Esr1 and Gper1. Conclusion: Our results show that ERβ has an important role in regulating ovulation in response to exogenous gonadotropins in 6-month-old mice, but not in younger mice. Our transcriptomic and immunohistochemical observations suggest a dysregulation of the granulosa cell communication and lack of tight coordination between granulosa cell replication and antrum expansion. A significant upregulation of other estrogen receptors supports a compensatory mechanism sustaining fertility during younger age in Esr2-KO mice.
2024-10-13 | GSE268029 | GEO
Project description:Breast cancer (BC) is the second most common type of cancer in women and one of the leading causes of cancer-related deaths worldwide. BC classification is based on the detection of three main histological markers: estrogen receptor alpha (ERα), progesterone receptor (PR) and the amplification of epidermal growth factor receptor 2 (HER2/neu). A specific BC subtype, named triple-negative BC (TNBC), lacks the aforementioned markers but a fraction of them express the estrogen receptor beta (ERβ). To investigate the functional role of ERβ in these tumors, interaction proteomics coupled to mass spectrometry (MS) was applied to deeply characterize the nuclear interactors partners in MDA-MD-468 and HCC1806 TNBC cells.
2019-12-03 | PXD014468 | Pride
Project description:The Estrogen Receptor beta (ERβ), is a member of the nuclear receptor superfamily of trancriptional regulators, with oncosuppressive activities, antagonizing hormone-induced carcinogenesis and inhibiting growth and oncogenic functions in breast cancers (BCs). It is able to exert specific biological functions also in the absence of estrogen stimuli. Interaction proteomics coupled to mass spectrometry (MS) was applied to deeply characterize the nuclear interactors cooperating with unliganded ERβ and the role of RNA in mediating these iteractions.
2017-12-19 | PXD006720 | Pride
Project description:The C4-12/Flag.ERβ cell line which stably expressed Flag.ERβ is used to study ERβ genomic functions without ERα interference. Mapping ERβ binding sites in these cells reveals ERβ unique distribution and motif enrichment patterns. Accompanying our mapping results, nascent RNA profiling is performed on cells at the same treatment time. The combined results allow the identification of ERβ target genes. Gene ontology analysis reveals that ERβ targets are enriched in differentiation, development and apoptosis. Concurrently, E2 treatment suppresses proliferation in these cells. Within ERβ binding sites, while the most prevalent binding motif is the canonical ERE, motifs of known ER interactors are also enriched in ERβ binding sites. Moreover, among enriched binding motifs are those of GFI, REST and EBF1, which are unique to ERβ binding sites in these cells. Further characterization confirms the association between EBF1 and the estrogen receptors, which favors the N-terminal region of the receptor. Furthermore, EBF1 negatively regulates ERs at the protein level. In summary, by studying ERβ genomic functions in our cell model, we confirm the anti-proliferative role of ERβ and discover the novel cross talk of ERβ with EBF1 which has various implications in normal physiology. C4-12/Flag.ERβ cells were treated with 10nM E2 (or ethanol as vehicle control) for 1 hour. Nuclei were extracted and processed with run-on assay. The resultant run-on RNA was reverse-transcribed to generate cDNA library which was subsequently sequenced by Illumina Genome Analyzer II or HiSeq2000. Two samples for each treatment were included in this experiment.
2013-06-21 | E-GEOD-48159 | biostudies-arrayexpress
Project description:The C4-12/Flag.ERβ cell line which stably expressed Flag.ERβ is used to study ERβ genomic functions without ERα interference. Mapping ERβ binding sites in these cells reveals ERβ unique distribution and motif enrichment patterns. Accompanying our mapping results, nascent RNA profiling is performed on cells at the same treatment time. The combined results allow the identification of ERβ target genes. Gene ontology analysis reveals that ERβ targets are enriched in differentiation, development and apoptosis. Concurrently, E2 treatment suppresses proliferation in these cells. Within ERβ binding sites, while the most prevalent binding motif is the canonical ERE, motifs of known ER interactors are also enriched in ERβ binding sites. Moreover, among enriched binding motifs are those of GFI, REST and EBF1, which are unique to ERβ binding sites in these cells. Further characterization confirms the association between EBF1 and the estrogen receptors, which favors the N-terminal region of the receptor. Furthermore, EBF1 negatively regulates ERs at the protein level. In summary, by studying ERβ genomic functions in our cell model, we confirm the anti-proliferative role of ERβ and discover the novel cross talk of ERβ with EBF1 which has various implications in normal physiology.
2013-06-21 | GSE48096 | GEO
Project description:The C4-12/Flag.ERβ cell line which stably expressed Flag.ERβ is used to study ERβ genomic functions without ERα interference. Mapping ERβ binding sites in these cells reveals ERβ unique distribution and motif enrichment patterns. Accompanying our mapping results, nascent RNA profiling is performed on cells at the same treatment time. The combined results allow the identification of ERβ target genes. Gene ontology analysis reveals that ERβ targets are enriched in differentiation, development and apoptosis. Concurrently, E2 treatment suppresses proliferation in these cells. Within ERβ binding sites, while the most prevalent binding motif is the canonical ERE, motifs of known ER interactors are also enriched in ERβ binding sites. Moreover, among enriched binding motifs are those of GFI, REST and EBF1, which are unique to ERβ binding sites in these cells. Further characterization confirms the association between EBF1 and the estrogen receptors, which favors the N-terminal region of the receptor. Furthermore, EBF1 negatively regulates ERs at the protein level. In summary, by studying ERβ genomic functions in our cell model, we confirm the anti-proliferative role of ERβ and discover the novel cross talk of ERβ with EBF1 which has various implications in normal physiology.
2013-06-21 | GSE48159 | GEO
Project description:The C4-12/Flag.ERβ cell line which stably expressed Flag.ERβ is used to study ERβ genomic functions without ERα interference. Mapping ERβ binding sites in these cells reveals ERβ unique distribution and motif enrichment patterns. Accompanying our mapping results, nascent RNA profiling is performed on cells at the same treatment time. The combined results allow the identification of ERβ target genes. Gene ontology analysis reveals that ERβ targets are enriched in differentiation, development and apoptosis. Concurrently, E2 treatment suppresses proliferation in these cells. Within ERβ binding sites, while the most prevalent binding motif is the canonical ERE, motifs of known ER interactors are also enriched in ERβ binding sites. Moreover, among enriched binding motifs are those of GFI, REST and EBF1, which are unique to ERβ binding sites in these cells. Further characterization confirms the association between EBF1 and the estrogen receptors, which favors the N-terminal region of the receptor. Furthermore, EBF1 negatively regulates ERs at the protein level. In summary, by studying ERβ genomic functions in our cell model, we confirm the anti-proliferative role of ERβ and discover the novel cross talk of ERβ with EBF1 which has various implications in normal physiology. C4-12/Flag.ERβ cells were treated with 10nM E2 for 1 hour then crosslinked with 1% formaldehyde; EtOH treatment was used as control. Crosslinked samples were processed for ChIP-seq and sequenced with Illumina Genome Analyzer II and aligned to hg18. QuEST was used as the peak-calling software, using default parameters recommended to analyze transcription factor ChIP-seq data. The entire ChIP-seq process was performed once on each sample (Vehicle or E2-treated).
2013-06-21 | E-GEOD-48096 | biostudies-arrayexpress
Project description:Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen and the estrogen receptor, in synergy with androgen, are essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen plays in prostate carcinogenesis, and the precise mechanisms involved, remain unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor Beta (ERβ) agonist (genistein) and the inhibitory action of an anti-estrogen (ICI 182, 780) in patient-derived PCa xenograft models mimicking localized and metastatic disease. In this study, we compared the gene expression profiles of treated and untreated PCa xenografts using microarrays to identify a unique set of genes that were both up-regulated by genistein treatment and down-regulated by the anti-estrogen, ICI 182,780. Five of the six genes identified from this comparison belonged to the metallothionein (MT) gene family. Knock-down of ERβ led to a reduction in MT gene expression, confirming its role in regulating these genes. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumour lines, both of which were originally derived from the same PCa patient. Together our data provides evidence for the role of ERβ signalling in PCa metastasis and implicates estrogen-stimulated MT gene expression in this process. Three samples each (total RNA extracted from three tumours of three different animals from each group) for control, genistein and ICI were used for the array.
2012-12-27 | E-GEOD-43146 | biostudies-arrayexpress