Characterization of ER, GR, and FoxA1 binding patterns in breast cancer cells treated with either Dex or E2
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE72249 | GEO | 2016/04/08
SECONDARY ACCESSION(S): PRJNA293471
REPOSITORIES: GEO
Similar Datasets
Project description:The estrogen receptor (ER), glucocorticoid receptor (GR), and forkhead box protein 1 (FoxA1) are significant factors in breast cancer progression. FoxA1 is well-established as a pioneer factor for steroid receptor recruitment to chromatin. Here we show that ER and GR have the ability to alter the genomic response of FoxA1 to specific binding sites within the genome. These findings alter the classical understood mechanism of FoxA1 establishing a dynamic transcription factor that can be regulated by hormones.
2016-04-08 | GSE72250 | GEO
Project description:The FOXA1 pioneer factor is an essential mediator of steroid receptor function in multiple hormone dependent cancers, including breast and prostate cancers, enabling nuclear receptors such as ER and AR to activate lineage specific growth programs. . Analyzing data from loss-of-function screens, we identified a subset of NSCLC tumor lines where proliferation is FOXA1-dependent. Using rapid immunoprecipitation and mass spectrometry of endogenous protein (RIME) we identified chromatin-localized interaction between FOXA1 and glucocorticoid receptor (GR) in these tumor cells. Knockdown of GR inhibited proliferation of FOXA1-dependent, but not FOXA1-independent NSCLC cells. Here, we utilized ChIP-sequencing to identify a permissive set of genes potentially regulated by FOXA1 and GR to understand potential mechanisms underlying FOXA1-GR dependence in NSCLC.
2022-05-16 | GSE203036 | GEO
Project description:The primordial actions of the estrogen receptor alpha (ER) in controlling breast cancer cells proliferation rate are particularly documented. However, reintroducing ER into ER-negative cells does not reprogram their transcriptome towards an estrogen-sensitive growth phenotype. Member of the Forkhead (FKH) family of transcription factors, FOXA1 has been characterized to be essential for the appropriate binding of ER onto chromatin in MCF-7 cells. FOXA1 pioneering actions involve modulations of histone post-translational modifications (HPTMs) and local depletion in methylated CpGs. Using MDA-MB231 cells which are ER and FOXA1 negative, we aimed at determining whether the introduction of ER and FOXA1 would be sufficient to restore an estrogen-sensitive growth and to coincidently reprogram chromatin. We used ChIP-seq experiments to map ER and FOXA1 binding sites (BSs) and to profile H3K4me2 and H3K27ac marks, and surprisingly observed that FOXA1 had rather a global negative impact on ER actions, associated with an inhibition of growth and a reorientation of the transcriptome of the cells towards cell death. We demonstrate that the re-introduction of FOXA1 in these cells actually competes for the binding and pioneering actions of FOXA2, another FKH protein, on a number of ER BSs. As demonstrated for its alter ego FOXA1 in MCF-7 cells, abrogating FOXA2 expression drastically diminished ER binding onto its cognate sites, associated with a local loss of HPTMs for active chromatin.
2022-12-11 | GSE55680 | GEO
Project description:The primordial actions of the estrogen receptor alpha (ER) in controlling breast cancer cells proliferation rate are particularly documented. However, reintroducing ER into ER-negative cells does not reprogram their transcriptome towards an estrogen-sensitive growth phenotype. Member of the Forkhead (FKH) family of transcription factors, FOXA1 has been characterized to be essential for the appropriate binding of ER onto chromatin in MCF-7 cells. FOXA1 pioneering actions involve modulations of histone post-translational modifications (HPTMs) and local depletion in methylated CpGs. Using MDA-MB231 cells which are ER and FOXA1 negative, we aimed at determining whether the introduction of ER and FOXA1 would be sufficient to restore an estrogen-sensitive growth and to coincidently reprogram chromatin. We used ChIP-seq experiments to map ER and FOXA1 binding sites (BSs) and to profile H3K4me2 and H3K27ac marks, and surprisingly observed that FOXA1 had rather a global negative impact on ER actions, associated with an inhibition of growth and a reorientation of the transcriptome of the cells towards cell death. We demonstrate that the re-introduction of FOXA1 in these cells actually competes for the binding and pioneering actions of FOXA2, another FKH protein, on a number of ER BSs. As demonstrated for its alter ego FOXA1 in MCF-7 cells, abrogating FOXA2 expression drastically diminished ER binding onto its cognate sites, associated with a local loss of HPTMs for active chromatin.
2022-12-11 | GSE55740 | GEO
Project description:Identifying FOXA1-GR transcriptional targets in FOXA1-GR dependent NSCLC
| PRJNA838217 | ENA
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. FoxA1 silenced breast cancer MCF-7 cell lines or control siRNA in the presence of Estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 6 h. There were three biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25315 | biostudies-arrayexpress
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts. breast cancer MCF-7 cell lines were treaated in the presence of Estrogen, Estrogen plus Tamoxifen, Tamoxifen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen or 1 microM Tamoxifen for 6 h. There were four biological replicates for each of the four different groups.
2010-11-17 | E-GEOD-25314 | biostudies-arrayexpress
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts.
2010-11-17 | GSE25315 | GEO
Project description:Estrogen Receptor-a (ER) is the key feature in the majority of breast cancers and ER binding to the genome correlates with the Forkhead protein FOXA1 (HNF3a), but mechanistic insight is lacking. We now show that FOXA1 is the defining factor that governs differential ER-chromatin interactions. We show that almost all ER-chromatin interactions and gene expression changes are dependent on the presence of FOXA1 and that FOXA1 dictates genome-wide chromatin accessibility. Furthermore, we show that CTCF is an upstream negative regulator of FOXA1-chromatin interactions. In ER responsive breast cancer cells, the dependency on FOXA1 for tamoxifen-ER activity is absolute and in tamoxifen resistant cells, ER binding occurs independently of ligand, but in a FOXA1 dependent manner. Importantly, expression of FOXA1 in non-breast cancer cells is sufficient to alter ER binding and response to endocrine treatment. As such, FOXA1 is the primary determinant that regulates estrogen-ER activity and endocrine response in breast cancer cells and is sufficient to program ER functionality in non-breast cancer contexts.
2010-11-17 | GSE25314 | GEO
Project description:Invasive Lobular Carcinoma (ILC) is the second most frequent breast cancer (BCa) type and encompasses 10-15% of BCa cases. FOXA1 specific mutations are enriched in this subtype of BCa, however their role in breast cancer pathogenesis is still ill-defined. FOXA1, together with estrogen receptor (ER), is a key transcription factor for the correct activation of estrogen-dependent gene expression and, consequently, for mammary gland development and BCa identity. FOXA1 has the capability to bind to and de-compact heterochromatin to render it accessible for other nuclear proteins, such as ER, and allow activation of their transcriptional programs upon estrogen stimulation. In this project, we aim to elucidate the role of FOXA1 missense mutations in altering its binding to DNA, chromatin accessibility, ER-dependent transcription and their implication in limiting the sensitivity to standard-of-care anti-hormonal therapy, commonly used in ER-positive BCa patients. To this end, we have generated BCa cell lines expressing these FOXA1 mutations and we will employ ATAC-Seq, RIME assays, ChIP-Seq and RNA-Seq to ascertain their effect on DNA accessibility, DNA binding capability, as well as binding of transcriptional coregulators, such as ER, to chromatin. We will extend our analyses to our internal BCa patient datasets with detailed clinical annotation to study the correlation between presence of FOXA1 mutations and response to anti-hormonal therapy of ER-positive BCa patients. The results of this project will allow to understand how the different mutations in the Forkhead domain can alter FOXA1 and ER function, transcriptional regulation and response to anti-hormonal therapy in ER-positive BCa patients.
2020-11-19 | GSE134655 | GEO