Arid1a deletion in collaboration with Pten deletion leads to ovarian tumorigenesis in mouse
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Ie-Ming Shih
PROVIDER: E-GEOD-56531 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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.
2014-04-05 | GSE56531 | GEO
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:ARID1A, which encodes a component of the SWI/SNF chromatin-remodeling complex, is commonly mutated in ovarian clear cell carcinoma and many other cancer types. We used label-free LC-MS/MS to identify ARID1A-dependent proteome changes in ovarian clear cell carcinoma cell lines. In our first analysis, we compared ARID1A-wildtype ovarian clear cell carcinoma cell line OVCA429 with or without ARID1A CRISPR knockout. In a complementary analysis, we compared ARID1A-mutated ovarian clear cell carcinoma cell line OVISE with or without ARID1A overexpression using a tet-inducible promoter.
2016-07-13 | MSV000079904 | MassIVE
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: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:ARID1A, encoding a subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated epigenetic regulators in human cancers. ARID1A is mutated in over 50% ovarian clear cell carcinoma, a disease currently has no effective therapy. Here we show that ARID1A-mutated ovarian cancer cells are selectively sensitive to inhibition of HDAC2 activity. HDAC2 interacts with EZH2 in an ARID1A status dependent manner. HDAC2 knockdown inhibits the growth of ARID1A inactivated by not proficient ovarian cancer cells. HDAC2 functions as a co-repressor of EZH2 to suppress the expression of EZH2/ARID1A target tumor suppressor genes such as PIK3IP1, an inhibitor of PI3K/AKT signaling, to inhibit proliferation and promote apoptosis. Indeed, a FDA-approved pan-HDAC inhibitor suberoylannilide hydroxamine (SAHA) significantly suppressed the growth and reduced the ascites of the ARID1A-inactivated ovarian cancers in both orthotopic and genetic mouse models. This correlated with a significant improvement of survival of mice bearing ARID1A-mutated ovarian cancers.
2018-03-09 | GSE107201 | GEO
Project description:Ovarian clear cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a genetically engineered mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolonged mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A-PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
2014-12-31 | GSE57380 | GEO
Project description:We treated 6-8 week old mice that had floxed alleles of both Apc and Pten (for both alleles in each case) that also carry an Ovgp1-iCre-ERT2 transgene, with one of two treatments; a third group received neither treatment. The Ovgp1-iCre-ERT2 expresses Cre recombinase fused to a tamoxifen-inducible fragment of the estrogen receptor, in tissues where the Ovgp1 gene (oviductal glycoprotein 1) is expressed, which is almost exclusively in mouse oviductal epithelium (equivalent to human fallopian tube epithelium = FTE). Treating the mice with tamoxifen permits the Cre recombinase to enter the cell nucleus and inactivate the Apc and Pten genes. Six of the mice were treated with intraperitoneal injection of tamoxifen (0.1g/kg of body weight) dissolved in corn oil on days 1 and 3 and developed oviductal tumors (OdT) yielding 6 of the samples. Four mice (yielding 5 samples) were instead injected with 50 million plaque-forming units of replication-incompetent AdCre into both ovarian bursal cavities on day 1, which inactivated Apc and Pten in the ovarian surface epithelium (OSE), and lead to ovarian tumors (OT). Ovaries were also harvested from four untreated 6-8 week old mice with the same genotype, with two ovaries from each mouse comprising one control sample. RNA was purified from tumor or normal tissue, and targets for Affymetrix arrays synthesized from the mRNAs. We used Affymetrix Mouse Gene 2.1 ST arrays, which hold 41345 probe-sets, but we largely analyzed just those 25216 probe-sets that were mapped to Entrez gene IDs. Raw data was processed with Robust Multi-array Average algorithm (RMA). Data is log2-transformed transcript abundance estimates. We fit a one-way ANOVA model to the three groups of samples. 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 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 also provide supplementary excel files that show our simple analysis of GSE6008, which consists of 99 human ovarian tumor samples of 4 types, and 4 normal ovary samples, where we fit an ANOVA model to the 5 groups. In yet another supplementary file we show the correlation between each human tumor and mouse tumor, where we correlate the difference in log2-transformed values of each tumor from the average of the normals for the same species, for just those genes that were 1-to-1 best homologs according to build 68 of NCBI's Homologene, in order to see how much the human tumors resemble the mouse tumors. Six oviductal tumor samples from 6 mice with conditional knockout of Apc and Pten driven by an Ovgp1-iCre-ERT2 transgene , 5 ovarian tumor samples from 4 mice with conditional knockout of Apc and Pten driven by injection of AdCre into both ovarian bursal cavities, and 4 normal ovary samples from 4 mice.
2016-08-25 | E-GEOD-80085 | biostudies-arrayexpress
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