Global mammary luminal cells gene expression data from C451A-ERα and WT female mice treated by E2 or E2+Pg during 21 days.
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PROVIDER: PRJNA596527 | ENA |
REPOSITORIES: ENA
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Project description:We used microarrays to detail the global programme of gene expression in mammary luminal cells C451A-ERα and WT female mice treated by E2 0.01 MG and E2 0.01 MG +Pg 1.5 MG during 21 days.
2019-12-19 | GSE142297 | GEO
Project description:Estrogen receptor alpha (ERα)-positive breast cancers, while initially being responsive, eventually develop resistance to ERα targeted therapies through ERα-dependent and ERα-independent mechanisms. Through functional genomic studies we report heretofore unrecognized role for the axon guidance dependence receptor UNC5A in fine-tuning estradiol (E2) and anti-estrogen response. Knockdown of the estradiol-inducible UNC5A caused unrestricted ERα signaling as evident from deregulated E2-regulated gene expression and E2-independent tumorigenesis accompanied with multi-organ metastatic spread in xenograft models. UNC5A-knockdown cells displayed luminal/basal hybrid phenotype characterized by elevated expression of basal/stem cell enriched ∆Np63 and ITGA6 (CD49f), anti-apoptotic BCL2, and the lymphangiogenic factor NTN4 but lower expression of luminal/alveolar differentiation-associated factor ELF5 while maintaining functional ERα. Thus, UNC5A is a new regulator of ERα with a tumor/metastasis suppressive activity. Significance: ERα signaling network plays a significant role in ~70% of breast cancers. While the signaling molecules that partner with ERα to augment E2-dependent signaling and promote breast cancer progression have been well studied, negative feedback proteins that attenuate ERα signaling and their contribution to breast cancer progression are yet to be identified. This study reports E2-inducible UNC5A as a critical attenuator of ERα signaling and its reduced expression in primary breast cancer is associated with poor outcome. UNC5A potentially controls ERα signaling by restricting PI3K/AKT:ERα crosstalk needed for E2-independent activity while simultaneously maintaining ERα-dependent luminal differentiation program. These findings have important implications in developing strategies to combat anti-estrogen resistance and to improve clinical utility of PI3K/AKT inhibitors.
2018-11-22 | GSE89700 | GEO
Project description:Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal breast cancer phenotype. Recently, we demonstrated that ERα binds chromatin in absence of ligand (apoERα) regulating transcription of protein-coding genes and several lncRNAs. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts representing a signature of luminal breast cancer genes. DSCAM-AS1 is a paradigmatic example of apoERα activity since its expression is largely unaffected by estrogenic treatment despite an E2-induced increment of ERα binding on its promoter. Analysing H3K27ac ChIP-Seq performed in hormone-deprived MCF-7, we identified a set of Super Enhancers (SEs) occupied by apoERα including one mapped in proximity of DSCAM-AS1. Using ChIP-qPCR, we validated ChIP-Seq signal of apoERα, p300 and CTCF at both DSCAM-AS1 TSS and at its associated SE. Furthermore, analysing MCF-7 ChIA-PET data and performing a 3C experiment, we confirmed a long range chromatin interaction between the SE and the DSCAM-AS1 TSS. Interestingly, CTCF binding downstream to DSCAM-AS1 shows an enrichment in hormone-depleted medium as compared to other experimental conditions, indicating that CTCF demarcates enhancer actions at DSCAM-AS1 locus. The analysis of this lncRNA provides a paradigm of transcriptional regulation of a luminal specific apoERα regulated lncRNA.
2018-02-06 | GSE108693 | GEO
Project description:Background: Estrogen receptor (ERα) and aryl hydrocarbon receptor (AHR) are two nuclear receptors involved in regulating gene expression. ERα and AHR are regulated by estradiol(E2) and TCDD respectively. They are also regulated by dietary ligands including 3,3´diindolylmethane (DIM) and resveratrol (RES). DIM is an ERα and AHR agonist, while RES is an ERα agonist and AHR antagonist. Few studies have investigated the impact of RES and DIM on ERα and AHR signaling at a genome-wide level. This study assessed ERα and AHR binding and associated gene expression changes after treatment of MCF-7 human breast cancer cells with DIM, RES, E2, TCDD, and E2+TCDD for 1 hour and 6 hours before ChIP and RNA sequencing respectively. Results: 88% and 86% of the ERα bound sites after RES and DIM overlapped with E2 ERα sites. RES and DIM resulted in 577 and 446 differentially expressed genes (DEGs) respectively compared to 866 after E2. 68% and 62.3% of the DEGs after RES and DIM were closest to an ERα binding site. Motif analysis indicated enrichment for AHRE motif among DIM ERα sites but not among E2 or RES ERα sites. Both DIM and E2+TCDD resulted in greater genome wide binding of AHR than TCDD. DIM and E2+TCDD resulted in 10546 and 8904 AHR and ERα co-occupied sites respectively. While co-occupied sites for both enriched for the AHR and ERE motif among others, DIM mediated co-occupied sites enriched for Tcfcp2l1, Tgif1, Gata3 motifs while E2+TCDD mediated ones enriched for the NF1 and Ppara motifs. Overlap of coregulated DEGs after DIM and E2+TCDD indicated 123 were the same among both with 81 and 85 unique coregulated DEGs respectively. Enrichment analysis indicated that more enrichment terms were different than similar for coregulated genes after E2+TCDD and DIM. Conclusions: AHR activation is responsible for DIM mediated reduced regulation of gene expression by ERα relative to E2 and only a subset of the DEG’s after DIM and RES are ERα targets indicating future studies into other transcription factors regulated by DIM and RES are needed for insights into the regulation of gene expression by these ligands.
2023-10-16 | GSE232234 | GEO
Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
2017-06-17 | GSE100131 | GEO
Project description:Estrogen receptor (ERα) is central in driving the development of hormone-dependent breast cancers. A major challenge in treating these cancers is to understand and struggle endocrine resistance. We have previously shown that the Megakaryoblastic Leukemia 1 (MKL1) protein, a master regulator of actin dynamic and cellular motile functions, directs down-regulation of ERα and hormonal escape of estrogen-responsive breast cancer cell lines. In the present study, we decipher the underlining mechanisms by tracking functional changes in ERα activity. We demonstrate through gene expression microarray analysis that the constitutive activation of MKL1 in ERα-positive MCF7 breast cancer cells induces a transition from a luminal to a basal-like phenotype and suppresses almost all regulations of gene expression by estrogen. Chromatin immunoprecipitation of DNA coupled to high-throughput sequencing (ChIP-Seq) shows a profound reprogramming in ERα cistrome associated with a massive loss of ERα binding sites (ERBSs) generally associated with lower ERα-binding activity. Novel ERBSs appear to be associated with EGF and RAS signaling pathways. ERα dynamic was further impacted by a displacement of its monomer/dimer equilibrium towards its monomer state, associated with a redistribution of the normally nuclear ERα protein to the entire cell volume. We next show that the combination of these remodeled dynamics of ERα alters its interactions with genomic and non-genomic partners. In particular, the formation of ERα/kinase complexes was promoted by the constitutive activation of MKL1. Hence, MKL1-induced transition of ER-positive breast cancer cells from luminal to basal-like phenotype shifts ERα activities from genomic to non-genomic function.
2019-09-11 | GSE107924 | GEO
Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERα in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERα+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERα expression pattern.
2021-05-05 | GSE173815 | GEO
Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERα in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERα+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERα expression pattern.
2021-05-05 | GSE173816 | GEO
Project description:Background: Aberrant DNA methylation is an epigenetic hallmark of most malignant tumors including breast cancer. However, the exact role of TET2-mediated DNA demethylation in ERα-positive luminal breast cancer is not well understood. Results: Here we showed by TCGA analyses that lower TET2 mRNA expression level is associated with worse clinical outcomes (i.e., overall survival) in ERα-positive but not ERα-negative breast cancer. Moreover, depletion of TET2 by CRISPR/Cas9 results in increased tumorigenesis capability of MCF7 cells in vitro. Whole genome bisulfite sequencing (WGBS) analysis revealed that DNA hypermethylation (gain-of-5mC) occurs within a subgroup of enhancers including estrogen responsive element (EREs) in MCF7 cells upon TET2 depletion. ChIP-seq and RNA-seq analysis showed that TET2 depletion impairs E2-induced ERα binding to these ‘gain-of-5mC’ EREs and gene transcription. Conclusions: Our data suggest that TET2-mediated enhancer DNA demethylation fine-tunes ERα-dependent and independent gene transcription in ERα-positive breast cancer cells.
2020-07-09 | GSE136673 | GEO
Project description:Estrogen (E2) signaling through its nuclear receptor, estrogen receptor α (ERα) increases insulin-like growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor (IGF1R). Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERα-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERα in mediating the IGF1 transcriptional vs. growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERαUtcKO) mice, which selectively lack ERα in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERα expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERα binding sites in uterine chromatin using ChIP-seq. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERα-mediated and ERα-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife.
2017-06-14 | GSE100023 | GEO