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A regulatory axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor alpha modulates the alternative transcriptome of luminal breast cancer

ABSTRACT: A regulatory axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor alpha modulates the alternative transcriptome of luminal breast cancer

PROVIDER: PRJNA851051 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19754156_1.fastq.gz	Fastqsanger.gz
	SRR19754156_2.fastq.gz	Fastqsanger.gz
	SRR19754157_1.fastq.gz	Fastqsanger.gz
	SRR19754157_2.fastq.gz	Fastqsanger.gz
	SRR19754158_1.fastq.gz	Fastqsanger.gz

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A regulatory axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor alpha modulates the alternative transcriptome of luminal breast cancer

Project description:The epithelial splicing regulatory proteins 1 and 2 (ESRP1/2) control the epithelial‐to‐mesenchymal transition (EMT) splicing program in cancer. However, their exact role in Breast Cancer (BC) remains under debate. Here, we report that ESRP1, but not ESRP2, is overexpressed in luminal BCs patients with poor prognosis and correlates with Estrogen Receptor α (ERα) mRNA levels. Analysis of ERα genome binding profiles in both cell lines and primary breast tumors showed its binding on both ESRP1 and ESRP2 promoters, and the expression of these genes strongly decreased by ERα silencing in hormone-deprived conditions (apoERα). The combined knock down of ESRP1/2 in MCF-7 cells followed by RNA-Seq, revealed the dysregulation of 754 genes expression, with a widespread alteration of alternative splicing events (ASEs) of genes involved in cell signaling, metabolism, cell growth, and EMT. Functional network analysis of ASEs that correlate with ESRP1/2 expression in ERα+ BCs showed RAC1 as the hub node in the protein-protein interactions altered by ESRP1/2 silencing. The comparison of apoERα- and ESRP-modulated ASEs revealed 63 commonly regulated events, including 27 detected both in primary BCs and endocrine resistant cell lines. Our data support a functional implication of the ERα-ESRP1/2 axis in the onset and progression of BC by controlling the splicing patterns of related genes.

2022-06-20 | GSE206474 | GEO

A Regulatory Axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor α Modulates the Alternative Transcriptome of Luminal Breast Cancer.

Project description:Epithelial splicing regulatory proteins 1 and 2 (ESRP1/2) control the splicing pattern during epithelial to mesenchymal transition (EMT) in a physiological context and in cancer, including breast cancer (BC). Here, we report that ESRP1, but not ESRP2, is overexpressed in luminal BCs of patients with poor prognosis and correlates with estrogen receptor α (ERα) levels. Analysis of ERα genome-binding profiles in cell lines and primary breast tumors showed its binding in the proximity of ESRP1 and ESRP2 genes, whose expression is strongly decreased by ERα silencing in hormone-deprived conditions. The combined knock-down of ESRP1/2 in MCF-7 cells followed by RNA-Seq, revealed the dysregulation of 754 genes, with a widespread alteration of alternative splicing events (ASEs) of genes involved in cell signaling, metabolism, cell growth, and EMT. Functional network analysis of ASEs correlated with ESRP1/2 expression in ERα+ BCs showed RAC1 as the hub node in the protein-protein interactions altered by ESRP1/2 silencing. The comparison of ERα- and ESRP-modulated ASEs revealed 63 commonly regulated events, including 27 detected in primary BCs and endocrine-resistant cell lines. Our data support a functional implication of the ERα-ESRP1/2 axis in the onset and progression of BC by controlling the splicing patterns of related genes.

| S-EPMC9319905 | biostudies-literature

Regulatory Sharing Between Estrogen Receptor α Bound Enhancers

Project description:Regulatory Sharing Between Estrogen Receptor α Bound Enhancers

| PRJNA613099 | ENA

Transcription profiling of mouse normal mammary gland epithelial populations: basal/myoepithelial, luminal estrogen receptor negative (ER-) and luminal estrogen receptor positive (ER+) cells

Project description:The goal of the experiment was to carry out a transcriptome analysis of the three main epithelial cell populations of the mouse mammary gland, the basal/myoepithelial, luminal estrogen receptor negative (ER-) and luminal estrogen receptor positive (ER+) cells, to identify cell-type specific differences in gene expression. Three replicates arrays were carried out for each of the three populations (a total of nine arrays). Each replicate was a genuine biological replicate from RNA harvested from completely independent cell preparations. Each sample was isolated from preparations of mammary epithelium derived fourth mammary fat pads of 8 * 10 week old virgin female FVB mice. Each preparation was from a pool of 10 * 20 animals (20 * 40 fat pads).

2009-04-20 | E-TABM-683 | biostudies-arrayexpress

Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ChIP-seq]

Project description:Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ChIP-seq]

| PRJNA613101 | ENA

Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ATAC-seq]

Project description:Regulatory Sharing Between Estrogen Receptor α Bound Enhancers [ATAC-seq]

| PRJNA613100 | ENA

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

Project description:Advanced breast cancers represent a major therapeutic challenge due to their refractoriness to treatment. Cancer-associated fibroblasts (CAFs) are the most abundant constituents of the tumor microenvironment and have been linked to most hallmarks of cancer. However, the influence of CAFs on therapeutic outcome remains largely unchartered. Here, we reveal that spatial coincidence of abundant CAF infiltration with malignant cells was associated with reduced estrogen receptor (ER)-α expression in luminal breast tumors. Notably, CAFs mediated estrogen-independent tumor growth by selectively regulating ER-α signaling. Whereas most prototypical estrogen-responsive genes were suppressed, CAFs maintained gene expression related to therapeutic resistance. A high-throughput drug screen in co-cultures identified effector pathways involved in the CAF-induced regulation of ER-α signaling. Among these, the transforming growth factor-β and the janus kinase signaling cascades were validated as actionable targets to counteract the CAF-induced ER-α modulation. Finally, genes that were downregulated in cancer cells by CAFs were predictive of poor response to endocrine treatment. In conclusion, our work reveals that CAFs directly control the luminal breast cancer phenotype by selectively modulating ER-α expression and transcriptional function, and further proposes novel targets to disrupt the crosstalk between CAFs and tumor cells to reinstate treatment response to endocrine therapy in patients.

2024-02-23 | GSE251644 | GEO

Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

Project description:Cancer-associated fibroblasts rewire the estrogen receptor response in luminal breast cancer, enabling estrogen independence

| PRJNA1055006 | ENA

Nuclear Estrogen Receptor alpha (ERα) interactome following estrogen and antiestrogen treatment.

Project description:The Estrogen Receptor alpha (ERα) controls key cellular functions in hormone responsive breast cancer by assembling in large functional multiprotein complexes. ERα ligands are classified as agonists and antagonist, according to the response they elicit, thus the molecular characterization of the of ERα nuclear iteractome composition following estrogen and antiestrogen stimulation whose is needed to understand their effects on estrogen target tissues, in particular breast cancer. To this aim interaction proteomics coupled to mass spectrometry (MS) was applied to map the ERα nuclear interacting partners in MCF7 breast cancer cell nuclei following estrogen and antiestrogen stimuli.

2020-09-02 | PXD018709 | Pride

TRPS1 modulates chromatin accessibility to regulate estrogen receptor (ER) binding and ER target gene expression in luminal breast cancer cells (ATAC-Seq)

Project description:Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by the estrogen receptor alpha (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this pathway, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution causes direct repression of ER targets and indirectly activates dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness.

2023-07-02 | GSE236175 | GEO

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