Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

ABSTRACT: Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating between driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATAC-seq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

PROVIDER: EGAS00001005235 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Json Xml

Similar Datasets

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-negative cell line RNA-seq]

Project description:GATA3 transcription factor is considered critical for luminal development and differentiation in normal and malignant mammary epithelial cells (MECs). The androgen receptor (AR) has also been associated with luminal gene expression profiles in breast cancer, independent of the estrogen receptor (ER), and has been shown to promote a basal to luminal phenotype transition in mouse MECs. To date, the potential interaction of GATA3 and AR in transcriptional regulation of lineage driver genes in breast cancer has never been investigated. Our unbiased proteomic analysis identified GATA3 as a novel AR interacting protein in a variety of breast cancer cell types regardless of ER expression. We showed that AR and GATA3 interact in the cytoplasm and nucleus of normal and malignant breast epithelia, an interaction increased by androgen treatment. Androgen stimulation of breast cancer cells also induced nuclear translocation of AR and GATA3 and resulted in enrichment of co-localized AR and GATA3 chromatin binding events. Using ER+ and/or ER- breast cancer cell lines and ER+ patient-derived xenograft (PDX) models of breast cancer, we identified a conserved subset of AR agonist-induced AR and GATA3 co-occupied cis-regulatory elements across all models. Knockdown experiments indicated that GATA3 acts as an AR co-regulator to upregulate transcription of known luminal-lineage genes (e.g. EHF, AQP3, and KDM4B) and downregulate basal-lineage genes (e.g. SMAD3 and ELK3). Also, we showed an induction in the chromatin accessibility at those subsets of common AR-GATA3 cis-regulatory elements, which drive the luminal lineage identity in breast cancer upon androgen stimulation. Collectively, AR-GATA3 interaction and function provide a mechanism underpinning epithelial breast cancer cells that are classified as having a luminal mature transcriptome independent of ER status, through regulating the expression of lineage-restricted markers.

2023-12-21 | GSE176006 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive cell line RNA-seq]

2023-12-21 | GSE176005 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive_PDX_GATA3_ChIP-seq]

2023-12-21 | GSE178254 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-positive_cell_line_GATA3_ChIP-seq]

2023-12-21 | GSE178253 | GEO

AR interacts with GATA3 to induce a luminal epithelial phenotype in breast cancer through regulation of lineage-restricted genes [ER-negative_cell_line_ChIP-seq]

2023-12-21 | GSE178248 | GEO

Targeted sequencing of 86 regulatory elements and 12 breast cancer genes

Project description:Detecting somatic mutations in 86 putative driver regulatory elements for breast cancer

2017-08-01 | E-MTAB-5710 | biostudies-arrayexpress

ChIP-seq study using a cell line model of ER_ AR+ molecular apocrine tumours (AR_FoxA1_molecular_apocrine)

Project description:Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER_ AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER_ AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers.

2012-02-18 | E-MTAB-986 | biostudies-arrayexpress

Single Cell ATAC Sequencing of Mouse Mammary Epithelial Cells

Project description:The mammary epithelial cell (MEC) system is a bi-layered ductal epithelial network consisting of luminal and basal cells, maintained by a lineage of stem and progenitor cell populations. Here, we used integrated single-cell transcriptomics and chromatin accessibility analysis to reconstruct the cell types of the mouse MEC system and their underlying gene regulatory features in an unbiased manner. We define differentiation states within the secretory type of luminal cells, which can be defined as a continuous spectrum of progenitor and mature secretory cells. By integrating single-cell transcriptomics and chromatin accessibility landscapes, we identified cis- and trans-regulatory elements that are differentially activated in the specific epithelial cell types and our newly defined luminal differentiation states. Our work provides an unprecedented resource to reveal cis/trans regulatory elements associated with MEC identity and differentiation that will serve as a valuable reference to determine how the chromatin accessibility landscape changes during breast cancer.

2020-09-14 | GSE157888 | GEO

Single Cell RNA Sequencing of Mouse Mammary Epithelial Cells

2020-09-14 | GSE157889 | GEO

Systematic identification of regulatory elements in conserved 3’-untranslated regions of human transcripts

Project description:We present a combined experimental/computational technology to reveal a catalogue of functional regulatory elements embedded in 3’UTRs of human transcripts. We used a bidirectional reporter system coupled with flow cytometry and high-throughput sequencing to measure the effect of short, non-coding vertebrate-conserved RNA sequences on transcript stability and translation. Information-theoretic motif analysis of the resulting sequence-to-gene-expression mapping revealed linear and structural RNA cis-regulatory elements that positively and negatively modulate the post-transcriptional fates of human transcripts.

2014-03-21 | GSE55396 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data