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Fra-2 overexpression upregulates pro-metastatic cell-adhesion molecules, promotes pulmonary metastasis and reduces survival in a spontaneous xenograft model of human breast cancer

ABSTRACT: The effect of Fra-2 overexpression in two stable Fra-2 overexpressing clones of the human breast cancer cell line MDA-MB-231 on survival and metastatic load was studied after subcutaneous injection into scid and E- and P-selectin deficient scid (select) mice. To identify Fra-2 target genes, we performed cDNA microarrays with mRNA isolated from xenograft tumour tissue. Fra-2 overexpression lead to a significantly shorter overall survival and a higher amount of spontaneous metastases in scid mouse lungs and compared to select mice indicating that Fra-2 regulates selectin binding sites on the tumour cell surface, which directly influence overall survival. By using cDNA microarray analysis of resected primary tumours a multitude of deregulated genes, which are known to be involved in metastasis formation

ORGANISM(S): Homo sapiens

PROVIDER: GSE148089 | GEO | 2020/04/06

REPOSITORIES: GEO

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Identification of Fra-1 and/or Fra-2 regulated genes in MDA-MB231 cells

Project description:In the paper "Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers" by Bejjani et al., we identified Fra-1 and/or Fra-2 target genes in MDA-MB-231 cells. si RNA against Fra-1 and against Fra-2 were transfected in MDA-MB-231 cells either independenlty or simultaneously to identify genes regulated specifically by Fra-1 or Fra-2 and genes regulated redundantly or complementarily by Fra-1 and Fra-2 total RNA were purified and biotinylated sense-strand cDNA were produced. cDNA targets were used to probe Affymetrix GeneChip Human Gene 2.0 ST arrays

2021-02-23 | GSE146823 | GEO

Comparative analysis of gene expression in Fra-1+/+ and Fra-1-/- mice lung

2014-05-22 | GSE43695 | GEO

Comparative analysis of gene expression in Fra-1+/+ and Fra-1-/- mice lung

Project description:We hypothesized that gene expression in lungs of Fra-1+/+ and Fra-1-/- mice are divergent thus contributing fibrosis. More specifically, Fra-1-/- mice are increased susceptible to fibrosis. In order to test these hypotheses at the gene expression level, we utilized microarray analysis to examine transcriptional differences between Fra-1+/+ and Fra-1-/- mice at early time point. This study utilizes microarray analysis to test these hypotheses. 5 days PBS and bleomycin treated lung samples from both Fra-1+/+ and Fra-1-/- mice were used. RNA was isolated and used for global gene expression profiling (Affymetrix MoGene 1.0ST v1 Array). The raw probe signal intensities were quantile normalized over all samples, summarized with the robust multi-array average (RMA) algorithm and log2 transformed with a median polish, using the Affymetrix Power Tools. We considered a transcript cluster (gene-level) to be reliably expressed in a sample if the Affymetrix implemented DABG (detection above ground) p-value was less than 0.05. We used local-pooled-error (LPE) estimates and robust statistical tests for evaluating significance of each gene's differential expression in a comparison.

2014-05-22 | E-GEOD-43695 | biostudies-arrayexpress

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

Transcript profiling in peritoneal macrophages from wildtype, Fra-1ΔMxCre or Fra-2ΔLysMCre mice

Project description:The polarization and activation of macrophages are controlled synergistically by transcription factors such as NF-κB and AP-1 transcription factor members. Surprisingly, little is known about the role of the Fra proteins, both members of the AP-1 transcription factor family, in macrophage activity. To determine the full profile of Fra network, microarray RNA expression analysis using Agilent Technologies platform was performed in wild-type, Fra-1ΔMxCre or Fra-2ΔLysMCre macrophages.

2021-05-17 | GSE128787 | GEO

Gene expression profile of Drosophila third instar larval wing imaginal discs overexpressing netrinA (netA) and frazzled (fra).

Project description:In order to analyze the global changes in gene expression resulting from induction of NetA-Fra signaling, we carried out a microarray experiment comparing Drosophila third instar wing imaginal discs in which Net+Fra had been overexpressed to age matched wild type wing imaginal discs. RNA extracted from both +NetA-Fra overexpression and wildtype third instar imaginal discs were hybridized to the Affymetrix GeneChip Drosophila Genome 2.0 . Heat shock induced GFP-marked clones ectopically expressing NetA+Fra in larvae were generated. Controls for this study included age matched wildtype third instar wing imaginal discs bearing GFP clones which were prepared in the same manner. Total RNA was extracted from dissected +NetA-Fra vs. control third instar wing imaginal discs and hybridized to the Affymetrix GeneChip Drosophila Genome 2.0.

2013-05-21 | E-GEOD-47113 | biostudies-arrayexpress

Gene expression profile of Drosophila third instar larval wing imaginal discs overexpressing netrinA (netA) and frazzled (fra).

2013-05-21 | GSE47113 | GEO

Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival

Project description:Background and Aim: Fra-1 (Fos-related antigen-1) is a member of the AP1 (activator protein-1) family of transcription factors. We have recently shown that Fra-1 is necessary for breast cancer cells to metastasize in vivo, and that breast cancer outcome can be predicted by a classifier comprising genes that are expressed in a Fra-1-dependent fashion. Here, we show that Fra-1 plays an important role also in colon cancer progression. Methods: We compared proliferation rates of parental and Fra-1-depleted colon cancer cells in vitro under 2D, 3D, and attachment-free conditions and in vivo upon subcutaneous and intravenous injections into mice. We also compared RNA expression profiles of colon cancer cells with and without Fra-1 expression. Results: Fra-1 depletion impair colony outgrowth of human colon cancer cells in soft agar and in suspension, whereas it does not affect proliferation on 2D culture plates. Consistent with this, upon subcutaneous injection into mice, tumors formed by Fra-1-depleted colon cancer cells are only three times smaller than those produced by control cells. In contrast, when injected intravenously, Fra-1 depletion causes 200-fold reduction in tumor burden. Consistent with the more aggressive characteristics of Fra-1-proficient tumors, the prognosis of colon cancer patients can be predicted by a Fra-1 classifier generated by comparing RNA profiles of parental and Fra-1-depleted colon cancer cells. Conclusions: Our results demonstrate that Fra-1 is an important determinant of the metastatic potential of human colon cancer cells, and suggest that a Fra-1 classifier can be used as a prognostic predictor in colon cancer patients.

2016-05-26 | GSE69415 | GEO

genome-wide mapping of Fra-1 and Fra-2 binding sites in MDA-MB-231 cell line

Project description:we report the mapping of Fra-1 and Fra-2 binding site on MDA-MB-231 cell line genome

2019-09-01 | GSE132098 | GEO

Gene expression profile of frazzled (fra) mutant Drosophila embryos

Project description:In order to analyze the global changes in gene expression resulting from loss of Fra signaling, we performed a microarray experiment comparing Drosophila embryos containing a loss of function fra[3] mutation to age matched wildtype embryos. RNA extracted from fra[3] mutant vs. wildtype embryos were hybridized to the Affymetrix GeneChip Drosophila Genome 2.0 . We selected Drosophila embryos at stage 13, which marks the onset of Fra expression in the embryonic CNS and the early stages of commissural axon guidance in the ventral nerve cord. RNA was extracted from both fra[3] and wildtype embryos. Hybridization experiments were performed on Affymetrix Drosophila Genome 2.0 microarrays.

2013-05-21 | E-GEOD-47112 | biostudies-arrayexpress

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