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Unknown,Transcriptomics,Genomics,Proteomics

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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: luca magnani

PROVIDER: E-GEOD-39418 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer.

Magnani Luca L Stoeck Alexander A Zhang Xiaoyang X Lánczky András A Mirabella Anne C AC Wang Tian-Li TL Gyorffy Balázs B Lupien Mathieu M

Proceedings of the National Academy of Sciences of the United States of America 20130401 16

The estrogen receptor (ER)α drives growth in two-thirds of all breast cancers. Several targeted therapies, collectively termed endocrine therapy, impinge on estrogen-induced ERα activation to block tumor growth. However, half of ERα-positive breast cancers are tolerant or acquire resistance to endocrine therapy. We demonstrate that genome-wide reprogramming of the chromatin landscape, defined by epigenomic maps for regulatory elements or transcriptional activation and chromatin openness, underli ...[more]

PMID: 23576735

Similar Datasets

Genome-wide reprogramming of the chromatin landscape underlies endocrine therapy resistance in breast cancer

Project description:The estrogen receptor alpha (ERa) drives the growth of two-thirds of all breast cancers. Endocrine therapy impinges on estrogen-induced ERa activation to block tumor growth. However, half of ERa-positive breast cancers are tolerant or acquire endocrine therapy resistance. Here we demonstrate that breast cancer cells undergo genome-wide reprogramming of their chromatin landscape, defined by epigenomic maps and chromatin openness, as they acquire resistance to endocrine therapy. This reveals a role for the Notch pathway while excluding classical ERa signaling. In agreement, blocking Notch signaling, using gamma-secretase inhibitors, or targeting its downstream gene PBX1 abrogates growth of endocrine therapy-resistant breast cancer cells. Moreover Notch signaling through PBX1 directs a transcriptional program predictive of tumor outcome and endocrine therapy response. Comparing histone modifications (H3K4me2 and H3K36me3), chromatin openness (FAIRE) and PBX1 binding between endocrine therapy sensitive MCF7 and resistant MCF7-LTED cells.

2013-05-01 | E-GEOD-37323 | biostudies-arrayexpress

Expression profile of the endocrine therapy resistant breast cancer cells LTED depleted of PBX1 or treated with the gamma-secretase inhibitor MRK003

Project description:Analysis of the response to PBX1 deprivation either using an siRNA approach or using a chemicalcompound indirectly targeting it. Deprivation of PBX1 is hypothesized to be essential for the growth of endocrine therapy resistant breast cancer cells (LTED) Total RNA was obtained from cells treated with siPBX1 or a control siRNA. The second set contains RNA from cells treated with MRK003 or a control (DMSO).

2013-05-01 | E-GEOD-36928 | biostudies-arrayexpress

The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer

Project description:This SuperSeries is composed of the following subset Series: GSE28006: The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [mRNA profiling] GSE28007: The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [ChIP-seq] Refer to individual Series

2011-09-29 | E-GEOD-28008 | biostudies-arrayexpress

Expression profile of the endocrine therapy sensitive breast cancer cells MCF7 depleted of PBX1

Project description:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with EGF. The hypothesis tested was that PBX1 is essential for EGF signaling in ERa positive breast cancer cells. Total RNA was obtained from MCF7 cells treated with siRNA directed at PBX1 or an siControl for 72h. Cells were then stimulated with estradiol (EGF) for 3h prior to RNA extraction.

2013-05-01 | E-GEOD-39417 | biostudies-arrayexpress

The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [mRNA profiling]

Project description:Effect of PBX1 silencing on global gene expression of MCF7 cells stimulated with estradiol. The hypothesis tested was that PBX1 is essential for estrogen signaling in ERa positive breast cancer cells. Total RNA was obtained from MCF7 cells treated with siRNA directed at PBX1 or an siControl for 72h. Cells were then stimulated with estradiol (E2) for 3h prior to RNA extraction.

2011-09-29 | E-GEOD-28006 | biostudies-arrayexpress

Expression data from MCF7 and LTED cells treated with YC-1

Project description:To identify novel therapeutic opportunities for patients with acquired resistance to endocrine treatments in breast cancer, we applied high-throughput screening to explore currently marketed drugs. The Ec50 values were determined for MCF7 and LTED cell lines to identify the compounds showing higher inhibition of LTED cells. The best compound was YC-1 and gene microarray studies were done in vitro for mechanistic exploration. MCF7 and LTED cells were treated with YC-1 for RNA extraction and hybridization on Affymetrix microarrays.

2014-03-17 | E-GEOD-38829 | biostudies-arrayexpress

Resistance to Palbociclib requires multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome

Project description:Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer. Despite the great efficacy of endocrine therapies, resistance remains a problem. Therefore, there is an immediate need for new, effective therapies in ER+ BC. In this study, we have explored the role of a potent CDK4/6 inhibitor called palbociclib. In order to identify alterations in protein abundance between the responsive and resistant setting, we generated a panel of palbociclib-sensitive and resistant cell lines and did quantitative, shotgun proteomics using dimethyl labelling. Palbociclib sensitive cell lines (wt-MCF7 or MCF7-LTED) were cultured in phenol red-free RPMI supplemented with 10% FBS and 1nM estradiol or 10% dextran-coated charcoal (DCC) respectively. Thereafter, palbociclib resistant cell lines were generated using 1μΜ palbociclib concentration. Samples were harvested at baseline and at the point of resistance.

2020-03-25 | PXD005611 | Pride

Proteomic characterization of ESR1 mutant cells

Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.

2024-03-26 | PXD032369 | Pride

Phosphoproteome characterization of ESR1 mutated breast cancer cells

2024-03-26 | PXD032285 | Pride

Modeling genome-wide transcriptional cis-regulation in n LNCaP-abl cell line after siRNA knock down of a series of gene factors [RNA-seq]

Project description:We describe, MARGE, Model-based Analysis of the Regulation of Gene Expression, a robust methodology that leverages a large library of genome-wide H3K27ac ChIP-seq profiles to predict key regulated genes and cis-regulatory regions in human or mouse. MARGE adopts a gene centric approach to define a regulatory potential that summarizes the aggregate activity of multiple cis-regulatory elements on each gene. This model is effective in describing cis-regulatory activity and, unlike the super-enhancer based approach, is highly predictive of gene expression changes in response to BET-bromodomain inhibitors. We show that linear combinations of H3K27ac defined regulatory potentials, selected from an extensive database of published H3K27ac profiles, can accurately model diverse gene sets derived from differential gene expression experiments. In addition, we demonstrate a novel semi-supervised learning approach for identifying transcription factor binding sites associated with the set of transcription factors that regulate the gene set. MARGE leverages published H3K27ac ChIP-seq data to enhance the interpretation of newly generated H3K27ac ChIP-seq profiles. MARGE can also be used to analyze gene expression studies, without the production of matched H3K27ac ChIP-seq data. Transcriptome profiling in LNCaP-abl cell line after siRNA knock down of a series of gene factors.

2016-05-16 | E-GEOD-72534 | biostudies-arrayexpress

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