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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: magnani luca

PROVIDER: S-ECPF-GEOD-28006 | biostudies-other |

REPOSITORIES: biostudies-other

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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

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

2011-09-30 | GSE28006 | GEO

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

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2011-09-30 | GSE28008 | GEO

The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [ChIP-seq]

Project description:We profiled global PBX1 binding in MCF7 cells. The hypothesis tested was that PBX1 binds regions that recruit ERa following estradiol stimulation. Profiling of PBX1 cistrome in MCF7 breast cancer cells

2011-09-29 | E-GEOD-28007 | biostudies-arrayexpress

The pioneer factor PBX1 guides a distinct ERa signaling in breast cancer [ChIP-seq]

Project description:We profiled global PBX1 binding in MCF7 cells. The hypothesis tested was that PBX1 binds regions that recruit ERa following estradiol stimulation.

2011-09-30 | GSE28007 | GEO

PBX1 genomic pioneer function drives ER? signaling underlying progression in breast cancer.

Project description:Altered transcriptional programs are a hallmark of diseases, yet how these are established is still ill-defined. PBX1 is a TALE homeodomain protein involved in the development of different types of cancers. The estrogen receptor alpha (ER?) is central to the development of two-thirds of all breast cancers. Here we demonstrate that PBX1 acts as a pioneer factor and is essential for the ER?-mediated transcriptional response driving aggressive tumors in breast cancer. Indeed, PBX1 expression correlates with ER? in primary breast tumors, and breast cancer cells depleted of PBX1 no longer proliferate following estrogen stimulation. Profiling PBX1 recruitment and chromatin accessibility across the genome of breast cancer cells through ChIP-seq and FAIRE-seq reveals that PBX1 is loaded and promotes chromatin openness at specific genomic locations through its capacity to read specific epigenetic signatures. Accordingly, PBX1 guides ER? recruitment to a specific subset of sites. Expression profiling studies demonstrate that PBX1 controls over 70% of the estrogen response. More importantly, the PBX1-dependent transcriptional program is associated with poor-outcome in breast cancer patients. Correspondingly, PBX1 expression alone can discriminate a priori the outcome in ER?-positive breast cancer patients. These features are markedly different from the previously characterized ER?-associated pioneer factor FoxA1. Indeed, PBX1 is the only pioneer factor identified to date that discriminates outcome such as metastasis in ER?-positive breast cancer patients. Together our results reveal that PBX1 is a novel pioneer factor defining aggressive ER?-positive breast tumors, as it guides ER? genomic activity to unique genomic regions promoting a transcriptional program favorable to breast cancer progression.

| S-EPMC3219601 | biostudies-literature

The pioneer factor PBX1 is a novel driver of metastatic progression in ERα-positive breast cancer.

Project description:Over 30% of ERα breast cancer patients develop relapses and progress to metastatic disease despite treatment with endocrine therapies. The pioneer factor PBX1 translates epigenetic cues and mediates estrogen induced ERα binding. Here we demonstrate that PBX1 plays a central role in regulating the ERα transcriptional response to epidermal growth factor (EGF) signaling. PBX1 regulates a subset of EGF-ERα genes highly expressed in aggressive breast tumours. Retrospective stratification of luminal patients using PBX1 protein levels in primary cancer further demonstrates that elevated PBX1 protein levels correlate with earlier metastatic progression. In agreement, PBX1 protein levels are significantly upregulated during metastatic progression in ERα-positive breast cancer patients. Finally we reveal that PBX1 upregulation in aggressive tumours is partly mediated by genomic amplification of the PBX1 locus. Correspondingly, ERα-positive breast cancer patients carrying PBX1 amplification are characterized by poor survival. Notably, we demonstrate that PBX1 amplification can be identified in tumor derived-circulating free DNA of ERα-positive metastatic patients. Metastatic patients with PBX1 amplification are also characterized by shorter relapse-free survival. Our data identifies PBX1 amplification as a functional hallmark of aggressive ERα-positive breast cancers. Mechanistically, PBX1 amplification impinges on several critical pathways associated with aggressive ERα-positive breast cancer.

| S-EPMC4673133 | biostudies-literature

TP53 engagement with the genome occurs in distinct local chromatin environments via pioneer factor activity.

Project description:Despite overwhelming evidence that transcriptional activation by TP53 is critical for its tumor suppressive activity, the mechanisms by which TP53 engages the genome in the context of chromatin to activate transcription are not well understood. Using a compendium of novel and existing genome-wide data sets, we examined the relationship between TP53 binding and the dynamics of the local chromatin environment. Our analysis revealed three distinct categories of TP53 binding events that differ based on the dynamics of the local chromatin environment. The first class of TP53 binding events occurs near transcriptional start sites (TSS) and is defined by previously characterized promoter-associated chromatin modifications. The second class comprises a large cohort of preestablished, promoter-distal enhancer elements that demonstrates dynamic histone acetylation and transcription upon TP53 binding. The third class of TP53 binding sites is devoid of classic chromatin modifications and, remarkably, fall within regions of inaccessible chromatin, suggesting that TP53 has intrinsic pioneer factor activity and binds within structurally inaccessible regions of chromatin. Intriguingly, these inaccessible TP53 binding sites feature several enhancer-like properties in cell types within the epithelial lineage, indicating that TP53 binding events include a group of "proto-enhancers" that become active enhancers given the appropriate cellular context. These data indicate that TP53, along with TP63, may act as pioneer factors to specify epithelial enhancers. Further, these findings suggest that rather than following a global cell-type invariant stress response program, TP53 may tune its response based on the lineage-specific epigenomic landscape.

| S-EPMC4315292 | biostudies-literature

Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.

Project description:TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-β signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-β signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-β signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription.

| S-EPMC6824466 | biostudies-literature

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