Arid1a deletion in collaboration with Pten deletion leads to ovarian tumorigenesis in mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE56531 | GEO | 2014/04/05
SECONDARY ACCESSION(S): PRJNA243644
REPOSITORIES: GEO
Similar Datasets
Project description:Mice developed ovarian tumors after Arid1a and Pten double knockout. Gene expression profiles of 5 such ovarian tumors were compared with those of 4 normal ovaries. The differentially expressed genes were then used to investigate the similarity between the mouse ovarian tumors and major subtypes of human ovarian cancers. Total RNA obtained from the mouse ovarian tumors developing after Arid1a and Pten knockout compared to normal mouse ovaries.
2014-04-05 | E-GEOD-56531 | biostudies-arrayexpress
Project description:We mated mice with floxed alleles of both Apc and Pten, to mice with floxed alleles for Arid1a, to obtain female mice with both copies of all three genes floxed. At 7 to 8 weeks of age the right ovarian bursal cavites of the mice were injected with 50 million plaque-forming units of adenovirus expressing Cre recombinase, which causes the floxed genes to be knocked out. Tumor tissue from 3 mice for each group was obtained at necropsy, RNA purified, and targets for Affymetrix arrays synthesized from the mRNAs. We used Affymetrix Mouse Genome 430 2.0 arrays, which hold 45101 probe-sets. Raw data was processed with Robust Multi-array Average algorithm (RMA). Data is log2-transformed transcript abundance estimates. We performed T-tests to compare the 3 vs 3 arrays. We supply a supplementary excel workbook that holds the same data as the data matrix file, but also holds the probe-set annotation at the time we analyzed the data, and some very simple statistical calculations, which select subsets of the probe-sets as differentially expressed. Consumers should consider obtaining more up-to-date probe-set annotation for the array platform. We have also supplied a second supplementary tar archive holding software and files to 1) perform permutation testing of the probe-set selection in order to estimate false discovery rates for the probe-sets we selected as differentially expressed, 2) perform enrichment testing of GO terms, and 3) to perform enrichment testing of KEGG pathways and 3000 curated gene sets from version 4 of the Molecular Signatures Database (MSigDB). The software is in "C". Ovarian endometrioid carcinoma samples from 3 female mice with conditional knockout of Apc and Pten, were compared to similar tumors from 3 female mice with conditional knockout of Apc, Pten, and Arid1a.
2015-08-04 | E-GEOD-67695 | biostudies-arrayexpress
Project description:We found that deleting Pten in Albumin expressing cells results in liver steatosis as early as 1 month of age. The mice develop hyperplasia and tumor phenotypes starting at 7-8 months of age. At 12 months and beyond, all mice develope spontanous liver tumors of mixed lineage phenotypes dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury. Pten is deleted specifically in the liver (Pten loxP/loxP; Alb-Cre+). Liver tissues were analyzed at 3 months (steatosis stage) and 15 months (tumor stage)
2015-12-31 | E-GEOD-70681 | biostudies-arrayexpress
Project description:We used microarrays to analyze the global gene expression and identified differentially expressed gene list between wild-type anterior prostates and Pb-Cre4;PtenLoxP/LoxP anterior prostates, Pb-Cre4;PtenLoxP/LoxP;LrfLoxP/LoxP anterior prostates at 12 weeks of age. Prostate-specific Pten deletion (Pb-Cre4;PtenLoxP/LoxP) results in prostate intraepithelial neoplasia (PIN) which, following a long latency, can progress to high-grade adenocarcinoma, albeit with minimally invasive and metastatic features. However, inactivation of Lrf in the prostate epithelium in combination of Pten results in aggressive prostate tumors. To understand the molecular mechanisms by which loss of Lrf promotes Pten-loss-driven prostate tumorigenesis, we conducted transcriptome comparison of three wild-type anterior prostates, three Pb-Cre4;PtenLoxP/LoxP PIN, and three Pb-Cre4;PtenLoxP/LoxP;LrfLoxP/LoxP anterior prostate tumors.
2013-05-19 | E-GEOD-46473 | biostudies-arrayexpress
Project description:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most mutated epigenetic regulator in human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with ARID1A mutational status remain a challenge. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated ovarian tumors. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumors. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylated the Lysine 120 residue of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’ apoptotic function by upregulating HDAC6. These results indicate that pharmacological inhibition of HDAC6 is a novel therapeutic strategy involving ARID1A-mutation
2017-07-14 | GSE84405 | GEO
Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.
2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress
Project description:We found that deleting Pten in Albumin expressing cells results in liver steatosis as early as 1 month of age. The mice develop hyperplasia and tumor phenotypes starting at 7-8 months of age. At 12 months and beyond, all mice develope spontanous liver tumors of mixed lineage phenotypes dihydrocollidine (DDC) shows that the primary effect of AKT2 loss is attenuation of hepatic injury and not inhibition of progenitor cell proliferation in response to injury.
2015-12-31 | GSE70681 | GEO
Project description:RNA-seq was carried out on prostate tumors from mice with prostate-conditional PTEN knockout with and without prostate-conditional FOXP1-SHQ1 locus deletion (12 month old PTEN-flox/flox Pb-Cre4 mice and FOXP1-SHQ1-flox/flox PTEN-flox/flox Pb-Cre4 mice )
2017-09-08 | GSE83358 | GEO
Project description:Illumina array was employed to analyze the genes whose expression are altered when ARID1A gene is downregulated by shRNA in normal ovarian surface epithelial cells OSE4 and IOSE80pc. This leads to discovery of p53-regulated genes such as p21 and SMAD3. ARID1A knockdown in OSE4 and IOSE80pc
2012-05-01 | E-GEOD-37684 | biostudies-arrayexpress
Project description:Normal human tissues are known to be composed of a pactchwork of mutant clones but with limited implications on cancer risk. PTEN and ARID1A deficient clones were detected in the human colon using immunohistrochemistry and were found to be the product of monoallelic loess. They were associated with a bias in clone dynamics which resulted in positive selection in the tissue. Heterozygous mutations were introduced in intestinal organoids which were subjected to bulk RNA-seq to describe the molecular mechanisms behind their positive selection. Although PTEN het organoids were associated with an advantageous phenotype in organoids, which was recapitulated in the transcriptomic analysis with increase proliferation and upregulation of developmental/regenerative processes and metabolic reprogramming, the ARID1A het organoids showed reduced growth which was seen as upregulation of apoptosis and downregulation of DNA replication. The discrepancy between the tissue and organoid phenotype for ARID1A was later explained due to the impact on stromal cells which are found in the tissue and are mediating the selective advantage. Importantly these molecular alterations and behaviours arise due to haploinsufficiency of these tumour suppressors in a pre-neoplastic context.
2024-05-13 | GSE266990 | GEO