Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

ABSTRACT: Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46440 | GEO | 2014/06/30

SECONDARY ACCESSION(S): PRJNA200345

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (expression)

Project description:Triple negative breast cancer (TNBC) is an aggressive clinical phenotype, and accounts for 15% to 20% of all breast cancers. The molecular determinants of malignant cell behaviors in TNBC remain largely unknown. We find that the AP-1 transcription factor component, Fra-1, is overexpressed in basal-like breast tumors, and its expression level has high prognostic significance. Depletion of Fra-1 or its heterodimeric partner c-Jun inhibits the proliferative and invasive phenotypes in TNBC cells. To gain insights into the transcriptional regulatory networks of AP-1 in TNBC cells, we combine genome-wide ChIP-seq with loss-of-function transcriptome analyses. We observe dysregulation of direct targets of the Fra-1/c-Jun heterodimer involved in cell proliferation, cell adhesion, and cell-cell contact. Intriguingly, we find that AP-1 mediates downregulation of E-cadherin through direct transcriptional induction of ZEB2. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and proliferative propensity. BT549 cells grown in complete medium were transfected with a control siRNA, siRNA targeting Fra-1 or siRNA targeting c-Jun for 72 h, and then global gene expression profiles were assessed. Three or four biological replicates were used for each group.

2014-06-30 | E-GEOD-46440 | biostudies-arrayexpress

Insights into the invasiveness of triple negative breast cancer from genome-wide profiling of transcription factor AP-1 (ChIP-seq)

2014-06-30 | GSE46166 | GEO

Blocking Fra-1 sensitizes triple-negative breast cancer to olaparib

Project description:Fra-1 (FOSL1) is overexpressed in triple-negative breast cancer (TNBC). Fra-1 is a member of the activator protein 1 (AP-1) transcription factor complex, which plays crucial roles in tumor progression and treatment resistance. We have previously identified 118 proteins that interact with endogenous chromatin-bound Fra-1 in TNBC cells in a large screen, and these included PARP1(Poly (ADP-ribose) polymerase 1). PARP1 inhibitor olaparib is currently in clinical use for treatment of BRCA-mutated TNBC breast cancer. Here, we demonstrate that this interaction impacts the efficacy of olaparib treatment. We corroborate that PARP1 interacts with Fra-1, and we show that PARP1 downregulates Fra-1 and consequently reduces AP-1 transcriptional activity. Inhibition of PARP1, on the other hand, increases Fra-1 levels and enhances its transcriptional activity, which in turn can increase treatment resistance. However, by inhibiting Fra-1, we found that TNBC cells became sensitized to olaparib treatment. We compared Fra-1 chromatin binding sites with the Fra-1 and PARP1 regulated transcriptomes, and found that a large fraction of PARP1-regulated genes was dependent on Fra-1. We further show that PARP1 protein levels significantly correlate with Fra-1 in clinical breast cancer tumors, and we identify that high PARP1 expression is indicative of a poor clinical outcome in breast cancer patients overall, but not in basal-like tumors. In conclusion, by exploring the functionality of the Fra-1 and PARP1 interaction, we propose that targeting Fra-1 could serve as a therapeutic approach to improve olaparib treatment outcome for TNBC patients.

2022-04-21 | GSE149621 | GEO

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

Project description:Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor growth. Here we report the identification of 118 proteins interacting with endogenous chromatin-bound Fra-1 in TNBC cells, highlighting DDX5 as the most enriched Fra-1-interacting protein. DDX5, a previously unrecognized protein in the Fra-1 transcriptional network, shows extensive overlap with Fra-1 cistrome and transcriptome that are highly associated with the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation. Furthermore, we show that the DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal-like tumors than in non-basal-like tumors, including luminal A, luminal B, and HER2-enriched subtypes. Collectively, by combining proteomic and genomic approaches we reveal a role for DDX5 as a regulatory protein of Fra-1 signaling and suggest DDX5 as a potential therapeutic target for TNBC.

2019-09-03 | GSE112963 | GEO

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1 [RNA-seq]

Project description:Fra-1, a member of the activator protein 1 (AP-1) family, is overexpressed in triple-negative breast cancer (TNBC) and plays crucial roles in tumor progression. However, a systematic analysis of the composition of the Fra-1 protein network specifically on chromatin is still missing. Here we performed endogenous purification of Fra-1 transcriptional complex under ChIP conditions, followed by mass spectrometry, to identify chromatin-bound partners of Fra-1 in TNBC cells. This study allowed the identification of 118 interactors, highlighting DDX5 as the high ranking of Fra-1 interacting proteins. DDX5, a previously unrecognized protein in the network, is recruited globally to Fra-1 binding sites and shares a substantial set of Fra-1 target genes required for the TNBC cell growth. We provide evidence that DDX5 expression enhances Fra-1 transcriptional activity, thereby enhancing Fra-1-driven tumorigenesis. By integrating ChIP-seq and RNA-seq, we show that DDX5 target gene signature predicts poor clinical outcome in breast cancer patients. DDX5 protein level was higher in triple-negative basal like tumors than in non-basal like tumors, including luminal A, luminal B and HER2-enriched subtypes. Collectively, this comprehensive Fra-1 interaction profiling provides a broad and deep view of Fra-1 chromatin interaction landscape, which will help in deciphering mechanisms of AP-1 regulation of gene expression.

2019-09-03 | GSE112962 | GEO

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1 [ChIP-seq]

2019-09-03 | GSE112961 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNFalpha can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically, we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response. BT549 cells were cultured to 50% confluency and transfected with control or c-Jun siRNA for 72 hours, followed by treatment with or without TNFÎ± for 6 hours.

2016-01-20 | E-GEOD-71915 | biostudies-arrayexpress

Liver cancer development driven by the AP-1/c-Jun~Fra2 dimer through c-Myc

Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the AP-1 (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens 1 and 2 (Fra-1/2) is unknown. Here we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis and Pparg-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently directly regulated by AP-1 through a conserved distal 3’ enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the BET bromodomain inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a novel model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

2024-04-22 | GSE261005 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [ChIP-seq]

Project description:Triple-negative breast cancer (TNBC) represents a highly aggressive form of breast cancer with limited treatment options. Proinflammatory cytokines such as TNF can facilitate tumor progression and metastasis. However, our knowledge of the molecular mechanisms underlying TNBC progression mediated by inflammation is still limited. Here, we define the AP-1 transcription factor c-Jun cistrome, which is comprised of 13800 binding sites responsive to TNFalpha-induced signaling in TNBC cells. In addition, we show that c-Jun regulates nearly a third of the TNFalpha-elicited transcriptome. Expression of the c-Jun-regulated pro-invasion gene program is strongly associated with clinical outcomes in TNBCs. Mechanistically; we demonstrate that c-Jun drives TNFalpha-mediated TNBC tumorigenicity by transcriptional regulation of Ninj1. As exemplified by the c-Jun bound CXC chemokine genes clustered on chromosome 4, we demonstrate that NF-kB might be a pioneer factor and is required for the regulation of TNFalpha-inducible inflammatory genes, whereas c-Jun has little effect. Together, our results uncover AP-1 as an important determinant for inflammation-induced cancer progression, rather than inflammatory response.

2016-01-20 | GSE71976 | GEO

Genome-wide profiling of inflammatory cistrome reveals AP-1/c-Jun as a key regulator of TNFalpha-mediated triple-negative breast cancer progression [microarray]

2016-01-20 | GSE71915 | GEO