Similar Datasets
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: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:The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice
| PRJNA486844 | ENA
Project description:The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice [RNA-seq]
| PRJNA486836 | ENA
Project description:The genome-wide enhancer profiling of breast cancer in the MMTV-PyVT mice [ChIP-seq]
| PRJNA486843 | ENA
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.
| S-EPMC10297447 | biostudies-literature
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.
| S-EPMC3929666 | biostudies-literature
Project description:Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K)/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN) activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1) and thioredoxin reductase (TrxR1) were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/Akt signalling pathway through a mechanism involving Trx1/TrxR1 redox regulations.
| S-EPMC2656613 | biostudies-literature
Project description:Aromatase inhibitors (AI) are extensively used in the treatment of estrogen receptor-positive breast cancers, however resistance to AI treatment is commonly observed. Apart from Estrogen receptor (ERα) expression, no predictive biomarkers for response to AI treatment are clinically applied. Yet, since other therapeutic options exist in the clinic, such as tamoxifen, there is an urgent medical need for the development of treatment-selective biomarkers, enabling personalized endocrine treatment selection in breast cancer. In the described dataset, ERα chromatin binding and histone marks H3K4me3 and H3K27me3 were assessed in a genome-wide manner by Chromatin Immunoprecipitation (ChIP) combined with massive parallel sequencing (ChIP-seq). These datasets were used to develop a classifier to stratify breast cancer patients on outcome after AI treatment in the metastatic setting. Here we describe in detail the data and quality control metrics, as well as the clinical information associated with the study, published by Jansen et al. [1]. The data is publicly available through the GEO database with accession number GSE40867.
| S-EPMC4536071 | biostudies-literature
Project description:Non-coding RNAs (ncRNAs) play major roles in development and cancer progression. To identify novel ncRNAs that may identify key pathways in breast cancer development, we performed high-throughput transcript profiling of tumor and normal matched-pair tissue samples. Initial transcriptome profiling using high-density genome-wide tiling arrays revealed changes in over 200 novel candidate genomic regions that map to intronic regions. Sixteen genomic loci were identified that map to the long introns of five key protein-coding genes, CRIM1, EPAS1, ZEB2, RBMS1, and RFX2. Consistent with the known role of the tumor suppressor ZEB2 in the cancer-associated epithelial to mesenchymal transition (EMT), in situ hybridization reveals that the intronic regions deriving from ZEB2 as well as those from RFX2 and EPAS1 are down-regulated in cells of epithelial morphology, suggesting that these regions may be important for maintaining normal epithelial cell morphology. Paired-end deep sequencing analysis reveals a large number of distinct genomic clusters with no coding potential within the introns of these genes. These novel transcripts are only transcribed from the coding strand. A comprehensive search for breast cancer associated genes reveals enrichment for transcribed intronic regions from these loci, pointing to an underappreciated role of introns or mechanisms relating to their biology in EMT and breast cancer.
| S-EPMC4370647 | biostudies-literature