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Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer

ABSTRACT: 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 cancers2–5, 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 risk–associated 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74718 | GEO | 2016/08/23

SECONDARY ACCESSION(S): PRJNA301239

REPOSITORIES: GEO

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Noncoding somatic and inherited single-nucleotide variants converge to promote ESR1 expression in breast cancer

Project description:Sustained expression of the estrogen receptor-Î± (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

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (ChIP-seq)

Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. Examination of genome-wide ZNF143 binding in MCF-7 cells

2016-08-09 | E-GEOD-76454 | biostudies-arrayexpress

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (RNA-seq)

Project description:Estrogen signaling in breast cancer cells relies on long-range chromatin interactions connecting distal regulatory elements bound by the estrogen receptor 1 (ESR1) to target gene promoters. This ensures stimulus and subtype-specific transcriptional responses. Expanding on the function of CTCF and the cohesin complex in breast cancer, we demonstrate that the chromatin-looping factor ZNF143 binds the promoter of most early-response estrogen target genes connected to distal regulatory elements in ESR1-positive breast cancer cells. Its chromatin occupancy is unaffected by estrogen stimulation, supporting a stable three-dimensional genomic architecture within the early response to estrogen. Its loss abrogates the estrogen-induced transcriptional response and growth of breast cancer cells. When taking into account CTCF, ZNF143 and cohesin complex subunits, we show that chromatin-looping factors are genetically altered in over 20% of ESR1-positive primary breast tumors. Furthermore, the overexpression of ZNF143, CTCF and RAD21, a cohesin complex subunit, in ESR1-positive breast tumors associates with a worse clinical outcome. Overall, our results suggest that ZNF143 is a new critical effector of the estrogen response and highlights the contribution of the chromatin looping machinery to ESR1-positive breast cancer development. mRNA profiles of MCF-7 cells (siCtl or siZNF143) under vehicle (EtOH) or E2 (10 uM 17-beta oestradiol) stimulation

2016-08-09 | E-GEOD-76453 | biostudies-arrayexpress

DNA methylation of estrogen regulated enhancers defines endocrine sensitivity in breast cancer

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

DNA methylation of estrogen regulated enhancers defines endocrine sensitivity in breast cancer

2015-07-01 | GSE69118 | GEO

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (ChIP-seq)

2016-08-09 | GSE76454 | GEO

The Chromatin-Looping Factor ZNF143 Engages at Looping Promoters to Favor the Estrogen Response in Breast Cancer (RNA-seq)

2016-08-09 | GSE76453 | GEO

Overexpression of NFIB and YBX1 in MCF-7 cells

Project description:Studying transcription factor (TF) interactions and gene regulatory networks in breast cancer, we have recently identified two distinct and opposing clusters of TFs associated with estrogen receptor-positive and -negative breast cancer and breast cancer risk. The relative activity of these two groups of TFs has a dramatic effect on patient outcomes and is likely to influence the phenotypic plasticity observed in breast cancer. We have identified two novel interactors (NFIB and YBX1) of the estrogen receptor (ESR1) using Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME), co-immunoprecipitation and microscopy experiments. Both NFIB and YBX1 are members of the group of risk TFs that oppose the activity of the risk TFs associated with estrogen receptor-positive disease, and we have demonstrated that they both repress the transcriptional activity of ESR1. Here, we examine the effect of NFIB and YBX1 overexpression on the transcriptome of an estrogen receptor-positive breast cancer cell line to see if these risk TFs are able to repress the ESR1 regulon and drive cells towards a less estrogen-dependent phenotype.

2017-07-01 | GSE95299 | GEO

Gene expression profiling of invasive breast cancer events from the tamoxifen prevention trial

Project description:Gene expression profiling of invasive breast cancer events from the tamoxifen prevention trial validates low estrogen receptor mRNA level as the main determinant of tamoxifen resistance in estrogen receptor positive breast cancer. In NSABP Breast Cancer Prevention Trial (BCPT), tamoxifen reduced the incidence of estrogen receptor (ER) positive tumors but not estrogen receptor negative breast cancer. More importantly, only 69% of estrogen receptor positive tumors were prevented by tamoxifen. The ER positive tumors arising in tamoxifen arm provides an ideal clinical model for acquired tamoxifen resistance. Based on data from NSABP trial B14 which showed linear prediction of the degree of benefit from adjuvant tamoxifen by the levels of ESR1 mRNA coding for ER-alpha, we hypothesized a priori that level of ESR1 mRNA would be lower in ER positive tumors arising in tamoxifen arm compared to those in placebo arm of BCPT. Keywords: Gene expression profiling analysis

2011-12-08 | GSE12665 | GEO

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer [RNA-seq]

Project description:Estrogen receptor alpha (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

2019-06-11 | GSE132428 | GEO

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