RNA analysis of Nr4a1 and Nr4a1-knockout mammary tumor cells from MMTV-PyVT transgenic mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE131895 | GEO | 2020/10/01
REPOSITORIES: GEO
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Project description:RNA analysis of Nr4a1 and Nr4a1-knockout mammary tumor cells from MMTV-PyVT transgenic mice
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Project description:Activation of transcription enhancers, especially super enhancers, is one of the important epigenetic features of tumorigenesis. However, only very few studies reported how the enhancer landscape evolves during tumorigensis. Here we utilized a proteomics approach and found that H3K27ac and H4K8ac are elevated in the mammary tumor of MMTV-PyVT mouse model, which was then confirmed by IHC results in human BRCA chips. ChIP-seq studies revealed that H4K8ac is highly co-localized with H3K27ac on chromatin, especially on the distal enhancers . We further identified a subgroup of super enhancers which are marked by H3K4me3 peaks in the intergenic regions. These H3K4me3-enriched super enhancers are covered with higher level of H3K27ac and H4K8ac in tumor than normal tissue , and accompanies higher transcription level of the adjacent genes. Combined with global gene expression data, we identified 148 tumor H3K4me3-enriched super enhancer adjacent genes with higher expression in the tumor tissues , which may be critical for breast cancer. We further utilized one inhibitor of p300, C646, to inhibit H3K27ac level, which successfully repressed tumor formation process probably through inhibiting Vegfa and other oncogenes. Taken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer, and raises the possibility of cancer treatment through modulating enhancer activity.
2019-08-18 | GSE118810 | GEO
Project description:Activation of transcription enhancers, especially super enhancers, is one of the important epigenetic features of tumorigenesis. However, only very few studies reported how the enhancer landscape evolves during tumorigensis. Here we utilized a proteomics approach and found that H3K27ac and H4K8ac are elevated in the mammary tumor of MMTV-PyVT mouse model, which was then confirmed by IHC results in human BRCA chips. ChIP-seq studies revealed that H4K8ac is highly co-localized with H3K27ac on chromatin, especially on the distal enhancers . We further identified a subgroup of super enhancers which are marked by H3K4me3 peaks in the intergenic regions. These H3K4me3-enriched super enhancers are covered with higher level of H3K27ac and H4K8ac in tumor than normal tissue , and accompanies higher transcription level of the adjacent genes. Combined with global gene expression data, we identified 148 tumor H3K4me3-enriched super enhancer adjacent genes with higher expression in the tumor tissues , which may be critical for breast cancer. We further utilized one inhibitor of p300, C646, to inhibit H3K27ac level, which successfully repressed tumor formation process probably through inhibiting Vegfa and other oncogenes. Taken together, our work identifies novel regulators and provides important resource to the genome-wide enhancer studies in breast cancer, and raises the possibility of cancer treatment through modulating enhancer activity.
2019-08-18 | GSE118802 | GEO
Project description:MicroRNAs (miRNAs) are small noncoding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs), controlling genes involved in a variety of cellular processes. miRNA dysregulation is recognized to play an essential role in the development and progression of cancer. MMTV-PyMT mice (Jax Strain: FVB/N-Tg(MMTV-PyVT)634Mul/J) are a well-characterized transgenic mouse model of breast cancer. Upon activation of the MMTV-PyVT transgene (mouse mammary tumor virus (MMTV) long terminal repeat upstream of a cDNA sequence encoding the Polyoma Virus middle T antigen (PyVT)) female carriers develop palpable mammary tumors as early as 5 weeks of age. We performed miRNA microarrays on samples from the MMTV-PyMT transgenic mouse model to investigate the differential expression of miRNAs during development of malignant disease in this model.
2017-08-23 | GSE68630 | GEO
Project description:Among genetically engineered mouse models of breast cancer, MMTV-PyVT is a mouse strain in which the oncogenic polyoma virus middle T antigen is driven by the mouse mammary tumor virus promoter. The aim of the present study was to perform morphologic and genetic analyses of mammary tumors arising from MMTV-PyVT mice. To this end, mammary tumors were obtained at 6, 9, 12, and 16 weeks of age for histology and whole-mount analyses. We conducted whole-exome sequencing to identify constitutional and tumor-specific mutations, and genetic variants were identified using the GRCm38/mm10 mouse reference genome. Using hematoxylin and eosin analysis and whole-mount carmine alum staining, we demonstrated the progressive proliferation and invasion of mammary tumors. Frameshift insertions/deletions (indels) were noted in the Muc4. Mammary tumors showed small indels and nonsynonymous single-nucleotide variants but no somatic structural alterations or copy number variations. In summary, we validated MMTV-PyVT transgenic mice as a multistage model for mammary carcinoma development and progression. Our characterization may be used as a reference for guidance in future research.
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Project description:Comparison the gene expression profiles of mouse mammary tumors derived from MMTV-PyMT transgenic in five different strains including FVB/NJ, I/LnJ F1, NZB/B1NJ F1, MOLF/Ei F1 and LP/J F1 and identification of signatures of tumor virulence. **NOTE: Migrated from caArray 1.x, identifier='gov.nih.nci.ncicb.caarray:Experiment:1015897560599049:1'
2015-06-20 | GSE70052 | GEO
Project description:The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice
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Project description:Nr4a1 deficient rats (Nr4a1-/-) were developed using the fawn hooded hypertensive rat (FHH), which provided a genetic background susceptible to kidney injury. Both groups of animals were evaluated for blood pressure, proteinuria, renal function, and whole transcriptome gene pathway changes. Gene expression profiling was performed at week 8, 16, and 24 using kidney from FHH and Nr4a1-/- rats. To identify differentially expressed gene between FHH and Nr4a1-/- two statistical methods were utilized: (1) FWER (family-wise error rate) procedure, p<0.05 and fold-change M-BM-11.2 or greater; and/or (2) Benjamani and Hochberg FDR (false discovery rate) using p<0.05, and fold-change M-BM-11.2 or greater. Two-way ANOVA using a p<0.01 or lower was performed to identify strain X time interaction effects between groups. Gene networks and functional analysis were evaluated through the use of Ingenuity Pathways Analysis . FHH and Nr4a1-/- rats were grown to 8, 16, and 24 weeks of age and kidney tissue was harvested for transcriptome analysis (n=3 replicates/ per group/ time)
2014-02-06 | E-GEOD-54714 | biostudies-arrayexpress
Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or Warburg effect in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML. To identify NR4A-dependent molecular signaling pathways that may control HSC homeostasis, we performed genome-wide transcript profiling of Lin-Sca1+ (LS) cells from WT and DKO mice. For Affymetrix analysis, we generated three independent pools of RNA from sorted LS cells from 10-20 WT or DKO (2- to 3-week-old) mice per sample.
2013-12-30 | E-GEOD-31042 | biostudies-arrayexpress
Project description:Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1(+/+) MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm(3) (SE, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm(3), 12 mice) were greatly reduced in AQP1(-/-) MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1(-/-) MMTV-PyVT mice, with reduced vessel density. HIF-1? expression was increased in tumors in AQP1(-/-) MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1(+/+) MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.
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