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Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (expression)

ABSTRACT: The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. MCF-7 cells were treated with either thiostrepton or DMSO for 6 hr. Each treatment was carried out in replicates of 6.

ORGANISM(S): Homo sapiens

SUBMITTER: Beraldi Dario

PROVIDER: S-ECPF-GEOD-40766 | biostudies-other |

REPOSITORIES: biostudies-other

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Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (expression)

Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. MCF-7 cells were treated with either thiostrepton or DMSO for 6 hr. Each treatment was carried out in replicates of 6.

2013-01-07 | E-GEOD-40766 | biostudies-arrayexpress

Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells.

Project description:BACKGROUND:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle. It is frequently over-expressed in cancer and is emerging as an important therapeutic target. In breast cancer FOXM1 expression is linked with estrogen receptor (ER?) activity and resistance to endocrine therapies, with high levels correlated with poor prognosis. However, the precise role of FOXM1 in ER positive breast cancer is not yet fully understood. RESULTS:The study utilizes chromatin immunoprecipitation followed by high-throughput sequencing to map FOXM1 binding in both ER?-positive and -negative breast cancer cell lines. The comparison between binding site distributions in the two cell lines uncovered a previously undescribed relationship between binding of FOXM1 and ER?. Further molecular analyses demonstrated that these two factors can bind simultaneously at genomic sites and furthermore that FOXM1 regulates the transcriptional activity of ER? via interaction with the coactivator CARM1. Inhibition of FOXM1 activity using the natural product thiostrepton revealed down-regulation of a set of FOXM1-regulated genes that are correlated with patient outcome in clinical breast cancer samples. CONCLUSIONS:These findings reveal a novel role for FOXM1 in ER? transcriptional activity in breast cancer and uncover a FOXM1-regulated gene signature associated with ER-positive breast cancer patient prognosis.

| S-EPMC3663086 | biostudies-literature

Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (expression)

2013-01-07 | GSE40766 | GEO

Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (ChIP-seq)

Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. The FOXM1-binding sites were mapped by ChIP-Seq in MCF-7 and MDA-MB-231 cells. Cells were treated either with thiostrepton, a FOXM1 inhibitor, or with DMSO (as control). Four replicates were performed in MCF7 cells and two replicates in MDA-MB-231 cells.

2013-01-07 | E-GEOD-40762 | biostudies-arrayexpress

Genome-wide mapping of FOXM1 binding reveals co-binding with oestrogen receptor alpha in breast cancer cells (ChIP-seq)

2013-01-07 | GSE40762 | GEO

Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells

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

2013-01-07 | E-GEOD-40767 | biostudies-arrayexpress

Genome-wide mapping of FOXM1 binding reveals co-binding with estrogen receptor alpha in breast cancer cells

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

2013-01-07 | GSE40767 | GEO

Genome-wide mapping of FOXM1 binding sites

Project description:There are nearly fifty forkhead (FOX) transcription factors encoded in the human genome and due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here we used ChIP-seq to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor which allows it to specifically control cell cycle-dependent gene expression.

2012-11-05 | GSE38170 | GEO

Genome-wide mapping of FOXM1 binding sites

2012-11-05 | E-GEOD-38170 | biostudies-arrayexpress

Co-regulated gene expression by oestrogen receptor α and liver receptor homolog-1 is a feature of the oestrogen response in breast cancer cells.

Project description:Oestrogen receptor α (ERα) is a nuclear receptor that is the driving transcription factor expressed in the majority of breast cancers. Recent studies have demonstrated that the liver receptor homolog-1 (LRH-1), another nuclear receptor, regulates breast cancer cell proliferation and promotes motility and invasion. To determine the mechanisms of LRH-1 action in breast cancer, we performed gene expression microarray analysis following RNA interference for LRH-1. Interestingly, gene ontology (GO) category enrichment analysis of LRH-1-regulated genes identified oestrogen-responsive genes as the most highly enriched GO categories. Remarkably, chromatin immunoprecipitation coupled to massively parallel sequencing (ChIP-seq) to identify genomic targets of LRH-1 showed LRH-1 binding at many ERα binding sites. Analysis of select binding sites confirmed regulation of ERα-regulated genes by LRH-1 through binding to oestrogen response elements, as exemplified by the TFF1/pS2 gene. Finally, LRH-1 overexpression stimulated ERα recruitment, while LRH-1 knockdown reduced ERα recruitment to ERα binding sites. Taken together, our findings establish a key role for LRH-1 in the regulation of ERα target genes in breast cancer cells and identify a mechanism in which co-operative binding of LRH-1 and ERα at oestrogen response elements controls the expression of oestrogen-responsive genes.

| S-EPMC3905875 | biostudies-literature

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