Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA395039 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To determine if ERG expression and PTEN loss were sufficient to transform prostate epithelial cells we constructed cell lines with expression of the TMPRSS2/ERG fusion gene (TE), stable knockdown of PTEN with shRNA (PTEN KD) or both alterations (PTEN KD/TE) using the PNT1A cell line. To determine what gene expression changes are associated the phenotypic changes between the cell line experimental groups, we carried expression microarray studies using Agilent 60K expression microarrays. RNAs from all four cell lines were analyzed in duplicate and probes with ≥ 1.4-fold or ≤0.7-fold relative to control cells identified. Our results demonstrated that PTEN loss and expression of the TMPRSS2/ERG fusion gene transform prostatic epithelial cells via enhanced FGF signaling.
2018-04-04 | GSE101635 | GEO
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen Test Cohort: 388 cases from the population based Swedish-Watchful Waiting cohort. The cohort consists of men with localized prostate cancer (clinical stage T1-T2, Mx, N0); Validation cohort: The PhysiciansM-bM-^@M-^Y Health Study (PHS) cohort included 116 US men diagnosed with incidental prostate cancer between 1983 and 2003; 455 cases were annotated for TMPRSS2-ERG fusion. Test Set: GSM208029 ... GSM208392 Validation Set: GSM208404 ... GSM208512
2008-05-27 | E-GEOD-8402 | biostudies-arrayexpress
Project description:Common epithelial cancers are believed to become more aggressive through the accumulation of multiple independent molecular events that lead to the deregulation of cell signaling. However, the discovery that the majority of prostate cancers harbor gene fusions of the 5'-untranslated region of androgen regulated TMPRSS2 promoter with ETS transcription factor family members has brought this paradigm into question1,2. TMPRSS2-ERG gene fusion is the most common molecular sub-type of prostate cancer. Recent work suggests that the TMPRSS2-ERG fusion is associated with a more aggressive clinical phenotype3. In the most advanced castration resistant prostate cancers where the androgen receptor has been inactivated, the TMPRSS2-ERG fusion remains functionally active. Here we show compelling clinical and gene expression data supporting the existence of a TMPRSS2-ERG fusion prostate cancer subclass. Using expression array profiling on 455 primary prostate tumors, we identified an 87 gene expression signature, distinguishing TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity. Computational analysis suggested that this fusion signature was associated with estrogen receptor signaling. Functional studies demonstrated regulation of the TMPRSS2-ERG fusion transcript by estrogenic compounds. These data identify a previously unrecognized mechanism for regulation of the TMPRSS2-ERG, even in the absence of a functional androgen receptor, and thus may have broader implications in the treatment of prostate cancer. Keywords: Prostate cancer, Expression array, Illumina, gene fusion, TMPRSS2, ERG, Signatures, Estrogen
2008-05-28 | GSE8402 | GEO
Project description:The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer but its role in disease progression is still debated. In this study, we uncovered a novel molecular mechanism promoting progression in ERG-fusion positive prostate cancer. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 mono- methylation prevents intra-domain interactions, favors DNA binding and promotes ERG transcriptional and oncogenic activity in cellular and mouse models. Consistently with the involvement in ERG oncogenesis, we found that K362 methylation was associated with disease progression in ERG transgenic mouse models and was enhanced by PTEN deficiency and AKT activation, which promoted EZH2 substrate switching from histone H3K27 to ERG. Conversely, EZH2 inhibition blocked ERG methylation along with ERG-induced transcriptional and phenotypic reprogramming in cell cultures and ERG/PTEN mice. We found that ERG and EZH2 co-occupy several genomic regions forming prevalently co-activating complexes. The network of ERG/EZH2 co-regulated target genes was enriched of functionally aggressive features and was associated preferentially with concomitant ERG gain and PTEN loss, castration-resistance and adverse clinical outcome in prostate cancer patients. Collectively, these findings identify ERG methylation as a novel post-translational modification sustaining disease progression in ERG-positive prostate cancers. Our data also provide an attractive rationale for developing molecularly targeted therapeutics to antagonize ERG oncogenic activity.
2021-04-16 | GSE159471 | GEO
Project description:Prostate tumors with the gene fusion TMPRSS2:ERG have been reported to have a significantly higher risk of recurrence compared with tumors lacking the fusion. Tumors from 139 patients who underwent radical prostatectomy were analyzed for the expression of 502 cancer-related genes to identify genes differentially regulated in TMPRSS2:ERG fusion tumors as well as identify biomarkers of biochemical recurrence. 139 prostate fresh-frozen tumors from radical prostatectomy surgery where profiled on the Illumina Human Cancer DASL Panel. 69 tumors were positive for the gene fusion TMPRSS2:ERG while 70 where not. 33 of the 139 patients experienced biochemical recurrence. Data was analyzed for differential genes in TMPRSS2:ERG fusion positive tumors as well as clinical and molecular biomarkers of recurrence.
2009-10-22 | E-GEOD-18655 | biostudies-arrayexpress
Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression.
2015-12-31 | GSE63070 | GEO
Project description:Here, we developed immunoprecipitation-mass spectrometry assays for the measurement of a low-abundance T1E4 TMPRSS2-ERG fusion protein, its isoforms and its interactome in VCaP prostate cancer cells.
2021-03-29 | PXD021236 | Pride
Project description:Lineage plasticity is a major mechanism driving prostate cancer progression and antiandrogen therapy resistance. Deletions or mutations in phosphatase and tensin homolog (PTEN) and TP53 tumor suppressor genes have been linked to lineage plasticity in prostate cancer. Fusion-driven overexpression of the E-twenty-six transformation specific (ETS)-related gene (ERG), encoding an oncogenic transcription factor, is observed in approximately 50% of all prostate cancers, yet its role in prostate cell lineage determination remains elusive. Here we demonstrate that transgenic expression of prostate cancer-associated ERG blocks Pten and Trp53 mutation-induced decreased expression of Ar and its downstream target genes and loss of luminal epithelial cell identity in the mouse prostate. Integrative analyses of ERG chromatin-immunoprecipitation sequencing (ChIP-seq) and transcriptome data show that ERG suppresses expression of a subset of cell cycle-promoting genes and RB phosphorylation, which in turn causes repression of E2F1-mediated expression of non-epithelial lineage genes. Xenograft studies show that PTEN/TP53 double mutated prostate tumors are responsive to the cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor palbociclib, but resistant to the AR inhibitor enzalutamide, while ERG/PTEN/TP53 triple-mutated prostate tumors behave completely opposite. Our studies identify ERG and the repressed cell cycle gene signature as intrinsic inhibitors of PTEN/TP53 double mutation-elicited lineage plasticity in prostate cancer. Our findings also suggest that ERG fusion can be utilized as a biomarker to guide the treatment of PTEN/TP53-mutated, RB1-intact prostate cancer with either antiandrogen or anti-CDK4/6 therapies.
2018-05-16 | GSE103871 | GEO
Project description:Prostate tumors with the gene fusion TMPRSS2:ERG have been reported to have a significantly higher risk of recurrence compared with tumors lacking the fusion. Tumors from 139 patients who underwent radical prostatectomy were analyzed for the expression of 502 cancer-related genes to identify genes differentially regulated in TMPRSS2:ERG fusion tumors as well as identify biomarkers of biochemical recurrence.
2009-10-23 | GSE18655 | GEO
Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression. Genotyped male mice were euthanized at 12 months of age and prostates isolated. Prostates were fixed overnight in 10% formalin and stored in 70% ethanol until tissue processing and paraffin embedding. Serial sections were cut from paraffin blocks which were stained for H&E and analyzed by a trained rodent histopathologist. Using these sections as a visual guide for specific types of lesions, the sequential sections were stained with hematoxylin and used for laser capture microdissection on ArcturusXT system. Epithelial cells within notable high grade prostate intraepithelial neoplasia (HG-PIN) lesions were microdissected from 3 mice from each corresponding genotype. In addition, poorly differentiated adenocarcinomas from PbCre;T-3Mb-Erg/+;PtenL/L mice were also dissected. RNA was isolated from the microdissected tissue using the Qiagen RNeasy FFPE kit and subjected to Nugen Amplification before microarray analysis on an Affymetrix Mouse Gene 2.0 ST chip.
2015-12-31 | E-GEOD-63070 | biostudies-arrayexpress