Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA284601 | ENA |
REPOSITORIES: ENA
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Project description:Expression of estrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy as part of their adjuvant care, but does not guarantee patient response. However, the molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here, we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at estrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1-activity; thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine responsive ESR1-positive cancer. Cumulatively these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy. Methylation profiling with Illumina's HumanMethylation450K array was performed on ESR1-positive hormone sensitive MCF7 cells, and three different well characterised endocrine resistant MCF7-derived cell lines; tamoxifen-resistant (TAMR), fulvestrant-resistant (FASR) and estrogen deprivation resistant (MCF7X) cells. For each cell line two biological replicates were profiled bringing the number of samples to eight.
2015-07-01 | E-GEOD-69118 | biostudies-arrayexpress
Project description:Expression of estrogen receptor (ESR1) determines whether a breast cancer patient receives endocrine therapy as part of their adjuvant care, but does not guarantee patient response. However, the molecular factors that define endocrine response in ESR1-positive breast cancer patients remain poorly understood. Here, we characterize the DNA methylome of endocrine sensitivity and demonstrate the potential impact of differential DNA methylation on endocrine response in breast cancer. We show that DNA hypermethylation occurs predominantly at estrogen-responsive enhancers and is associated with reduced ESR1 binding and decreased gene expression of key regulators of ESR1-activity; thus providing a novel mechanism by which endocrine response is abated in ESR1-positive breast cancers. Conversely, we delineate that ESR1-responsive enhancer hypomethylation is critical in transition from normal mammary epithelial cells to endocrine responsive ESR1-positive cancer. Cumulatively these novel insights highlight the potential of ESR1-responsive enhancer methylation to both predict ESR1-positive disease and stratify ESR1-positive breast cancer patients as responders to endocrine therapy.
2015-07-01 | GSE69118 | GEO
Project description:Around 35% of Estrogen Receptor (ER) positive patients develop resistance and relapse, highlighting the need to further understand the mechanisms underpinning endocrine resistance in breast cancer. Here, we study 3-dimensional (3D) epigenome remodelling in endocrine resistant breast cancer cells. We show that chromatin interactions both within and between topologically associating domains (TADs) frequently change in resistant breast cancer cells and that alterations in active (A-type) and inactive (B-type) chromosomal compartments are associated with decreased ER binding and atypical interactions and gene expression. Finally, we identify differentially interacting ER-bound regions that preferentially connect active enhancers and promoters associated with altered expression of ER-regulated genes. Importantly, interactions specifically associated with endocrine resistance, often occur coincidently with hypermethylation of ER binding. Our results demonstrate that 3D epigenome remodelling is a key mechanism of endocrine resistance that consists of differential chromatin interactions and aberrant DNA methylation at ER-regulated enhancer regions.
2019-12-11 | GSE130916 | GEO
Project description:Endocrine therapy is the most used treatment for hormone receptor positive breast cancers. Despite the clear benefit of endocrine therapy for patients with ER+ breast cancer, resistance to treatment is a critical clinical issue affecting a large number of patients. While many studies have shown that genetics is an important factor in therapy resistance, recent publications have also reported that epigenetics might play a major role in the acquisition of resistance to endocrine therapies. This role is exploited both at the DNA methylation level, with activation of oncogenes and silencing of tumor suppressor genes, and at the histone modification level, with changes in chromatin accessibility. DNA methylation exerts its role in resistance both by targeting the ER itself, by inducing promoter methylation, and genome wide, by changing the methylation levels of estrogen response elements. To better understand resistance acquisition in an in vitro setting, researchers developed cellular models of endocrine therapy resistance. The prevalent strategy to identify mechanisms of resistance development and novel targets involved in the process has been to study differences between resistant and sensitive cells. Here, we performed time-resolved DNA methylation profiling of development of resistance to tamoxifen treatment and to estrogen deprivation in the T47D luminal A breast cancer cell line with the aim to identify novel drivers.
2020-07-17 | GSE154626 | GEO
Project description:Breast cancers exhibit genome-wide aberrant DNA methylation patterns. To investigate how these affect the transcriptome and which changes are linked to transformation or progression, we apply genome-wide expression-methylation quantitative trait loci (emQTL) analysis between DNA methylation and gene expression. On a whole genome scale, in cis and in trans, DNA methylation and gene expression have remarkably and reproducibly conserved patterns of association in three breast cancer cohorts (n=104, n=253 and n=277). The emQTL associations form two main clusters, one relates to tumor infiltrating immune cell signatures and the other to estrogen receptor signaling. In the estrogen related cluster, using ChromHMM segmentation and transcription factor ChIP-seq data, we identify transcriptional networks regulated in a cell lineage-specific manner by DNA methylation at enhancers. These networks are strongly dominated by ERα, FOXA1 or GATA3 and their targets were functionally validated using knock-down by siRNA or GRO-seq analysis after transcriptional stimulation with estrogen.
2017-11-15 | GSE84207 | GEO
Project description:A critical mechanism for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and is recruited globally to ER binding regions. Interestingly, we identify differential motif enrichment between unique ER binding regions and unique c-Jun binding regions, with FoxA1 motif enriched in both sets of binding regions, whereas GATA3 motif only specifically enriched in the unique ER binding regions but not in the unique Jun binding regions. We demonstrate that the primary mechanism for estrogen/ER-dependent transcriptional responses is the tethering of ER to DNA under conditions where it cooperates with AP-1. We provide evidence that c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated omics data reveal TGFBI as one of the most perturbed genes regulated by c-Jun. TGFBI knockdown suppresses the growth of breast cancer cells and is critical for increasing the sensitivity of tamoxifen-resistant cells to tamoxifen. We show that TGFBI expression is elevated in breast cancer than in normal breast and the basal-like tumors express high levels of TGFBI. TGFBI expression is associated with poor patient survival in ER+ breast cancer receiving endocrine therapy, highlighting a role of AP-1 via TGFBI signaling as a major determinant of endocrine response in ER+ breast tumor.
2018-03-02 | GSE102410 | GEO
Project description:Postmenopausal breast cancer patients benefit from aromatase inhibitors (AIs) that reduce the levels of estrogens critical for the growth of estrogen receptor (ER)-positive tumors. Unfortunately, many tumors are resistant to AI, and we are only beginning to understand the complex mechanisms underlying treatment resistance. Here we set out to determine whether epigenetic changes could contribute to therapy resistance. For AI-resistance models, we used previously established MCF-7 cell clones, termed C4-12 and long-term estrogen deprivation (LTED), that were isolated after being cultured in estrogen-free media for 9 months and 18M-bM-^@M-^S24 months, respectively. Methyl CpG Binding Domain (MBD) - pull down followed by affymetrix promoter array was used to detect promoter methylation patterns in these cell lines. These studies identified widespread genomic hyper- and hypomethylation events, with a significant enrichment of promoter hypermethylation of development-associated genes in both cell lines. A developmentally regulated gene that was heavily methylated and lost expression in both cell-line systems was HOXC10. Moreover, we found that HOXC10 is an estrogen-regulated gene and lack of ER regulation is associated with progressive epigenetic silencing through EZH2/H3K27me3 and DNA hypermethylation. Stable knockdown of HOXC10 in MCF-7 cells resulted in increased cell growth, reduced cell apoptosis, and increased cell motility. A preliminary study using AI-treated breast tumors did not show significant associations, however, the numbers were small. We identified HOXC10 methylation as a novel determinant of endocrine resistance. Also, we revealed that epigenetic reprogramming of genes involved in development may be a fundamental phenomenon in hormone resistance. Therefore, our study might provide the basis for the expansion of clinical markers for endocrine resistance and future clinical trials such as combination of endocrine and epigenetic therapies. Long-term estrogen deprived previously established MCF-7 cell clones termed C4-12 and LTED genomic DNA subjected to Methyl CpG Binding Domain (MBD) - pull down followed by affymetrix promoter array to detect promoter methylation patterns
2014-05-01 | E-GEOD-39783 | biostudies-arrayexpress
Project description:The ETS transcription factor ELF5 drives mammary alveolar development in preparation for lactation by forcing differentiation within the progenitor cell population. In luminal A breast cancer, early disease progression is predicted by high levels of ELF5, and in preclinical models elevated ELF5 is associated with its two key features, the acquisition of resistance to endocrine therapy and increased metastasis. We first created an MCF7 cell line with doxycycline-inducible ELF5 and then examined with ChIP-seq differences in genomic binding of FOXA1, ER and H3K4me3 upon doxycycline treatment, compared to vehicle. In addition we performed RNA-seq experiments to examine changes in gene expression upon induction of ELF5 expression. Here we demonstrate that ELF5 binding overlaps with FOXA1 and ER at enhancers and promoters, and when elevated causes FOXA1 and ER to bind to new regions of the genome involved in resistance to endocrine therapy. RNA-seq demonstrated that these changes altered gene expression to diminish estrogen influence, and that ELF5 regulated the expression of ER transcription-complex genes. These data show that ELF5 modulated estrogen-driven transcription in breast cancer by directing FOXA1 and ER to new genomic locations, and by interaction with, and regulation of, members of the ER transcriptional complex. This provides a mechanistic basis for the influence of ELF5 on the progression of luminal breast cancer to endocrine insensitivity.
2020-01-06 | E-MTAB-7641 | biostudies-arrayexpress
Project description:Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program1. Somatic copy number alterations involving the ESR1 gene occur in approximately 1 % of ESR1-positive breast cancers2â5, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer riskâassociated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer. RNA-Seq was performed in HCC1419 cells heterozygous for the functional SNV, rs9383590, to determine which genes displayed an allelic imbalance within a 1MB window.
2016-08-23 | E-GEOD-74718 | biostudies-arrayexpress
Project description:Endocrine therapy resistance is a clinical problem for the management of estrogen receptor (ER)-positive breast cancer. The elucidation of factors that modulate ER signaling will provide useful information for understanding the pathophysiology of ER-positive and endocrine-resistant breast cancers. In the screen of estrogen-inducible lncRNAs transcribed from ER alpha-associated active promoters/enhancers, a novel estrogen-inducible lncRNA BNAT1 (breast cancer natural antisense transcript 1), which is transcribed from the proximal promoter region of COL18A1, was identified in ER+ MCF7 cells. siRNA-mediated BNAT1 silencing significantly inhibited the in vitro and in vivo growth of tamoxifen-resistant MCF7 cells.To examine the role of long non-coding RNA BNAT1 (alias gene name COL18AS was used in this dataset) in ER+ breast cancer, MCF7 cells were treated with siRNAs targeting BNAT1 (siCOL18AS, or siBNAT1) or control siRNA (siCtrl, or siControl). The microarray study showed that BNAT1 was closely associated with estrogen signaling pathway.
2025-08-31 | GSE212683 | GEO