E-GEOD-31812
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA145251
PROVIDER: E-GEOD-31812 | ExpressionAtlas | 2015-08-17
REPOSITORIES: ExpressionAtlas
Similar Datasets
Project description:Mutant p53 Disrupts Mammary Acinar Morphogenesis via the Mevalonate Pathway
| PRJNA145251 | ENA
Project description:p53 is a frequent target for mutation in human tumors and previous studies have revealed that these missense mutant proteins can actively contribute to tumorigenesis. To elucidate how mutant p53 might contribute to mammary carcinogenesis we employed a three-dimensional (3D) culture model. In 3D culture non-malignant breast epithelial cells form structures reminiscent of acinar structures found in vivo, whereas breast cancer cells form highly disorganized and in some cases invasive structures. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the sterol biosynthesis, or mevalonate, pathway as significantly upregulated by a tumor-derived mutant p53. Using statins and sterol biosynthesis intermediates, we demonstrate that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with the sterol gene promoters at least partly via the SREBP transcription factors. Finally, p53 mutation correlates with higher levels of sterol biosynthesis genes in human breast tumors. This activity of mutant p53 not only contributes insight into breast carcinogenesis, but also implicates the mevalonate pathway as a new therapeutic target for tumors bearing such mutations in p53.
2012-02-13 | GSE31812 | GEO
Project description:p53 is a frequent target for mutation in human tumors and previous studies have revealed that these missense mutant proteins can actively contribute to tumorigenesis. To elucidate how mutant p53 might contribute to mammary carcinogenesis we employed a three-dimensional (3D) culture model. In 3D culture non-malignant breast epithelial cells form structures reminiscent of acinar structures found in vivo, whereas breast cancer cells form highly disorganized and in some cases invasive structures. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the sterol biosynthesis, or mevalonate, pathway as significantly upregulated by a tumor-derived mutant p53. Using statins and sterol biosynthesis intermediates, we demonstrate that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with the sterol gene promoters at least partly via the SREBP transcription factors. Finally, p53 mutation correlates with higher levels of sterol biosynthesis genes in human breast tumors. This activity of mutant p53 not only contributes insight into breast carcinogenesis, but also implicates the mevalonate pathway as a new therapeutic target for tumors bearing such mutations in p53. RNA was isolated from three independent experiments of MDA-468.shp53 cells cultured under 3D conditions for 8 days in the presence or absence of DOX, reversed transcribed and hybridized to an Affymetrix GeneChip expression array. Data was processed using the Robust Multichip Average (RMA) algorithm to give expression signals and paired t-test was applied for each probe. Probes with 1% significance were selected for Ingenuity Pathway Analysis.
2012-02-13 | E-GEOD-31812 | biostudies-arrayexpress
Project description:In human breast cancer, mutations in the p53 gene are associated with poor prognosis, suggesting a mutant p53 “gain of function”. To study this phenomenon, we co-expressed mutant p53R270H in mice in which SV40 early proteins initiate the development of mammary adenocarcinomas in descendants of mammary epithelial cells that survived involution (WAPT-mice). This model allows the characterization of mammary carcinomas that developed in the absence or presence of mutant p53, while the endogenous wild-type p53 is functionallycompromised. Co-expression of mutant p53 significantly aggravated the phenotype of bitransgenic mice, as evidenced by a higher tumor incidence, a worse clinical staging and histological grading, as well as an enhanced invasiveness of the tumors, and more frequent pulmonary metastasis. Our data indicate that mutant p53 does not exert this effect by increasing genomic instability. On the contrary, lower grade tumors in WAP-T mice generally accumulated more amplifications of pro-survival genes than the corresponding tumors in bitransgenic animals, suggesting that mutant p53 can compensate for such genetic alterations by alternative mechanisms, possibly by its transcriptional activities, and thereby facilitate tumor formation. As a common feature and associated with their enhanced invasiveness, high grade tumors showed high level amplification of the Met-locus. Keywords: mutant p53, SV40 early proteins, tumor progression, tumor grade, tumor stage, mammary carcinoma, animal model, Met
2007-12-31 | GSE7135 | GEO
Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-κB subunit. Moreover, it partly shifts p53’s conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator.
2018-10-25 | PXD003120 | Pride
Project description:The Wnt/β-catenin signaling pathway is crucial for the development of variety of organs including the mammary gland. However, the precise role of Wnt/β-catenin signaling during embryonic mammary gland morphogenesis is still poorly understood. Here, we used an epithelial gain-of-function β-catenin mouse model to study the role of Wnt/β-catenin signaling in embryonic mammary gland development and profiled the transcriptomes of E13.5 and E16.5 control and mutant mammary epithelia.
2023-11-23 | GSE236630 | GEO
Project description:The identification of genes driving organ development is central to understanding which signaling pathways drive the pathogenesis of various diseases including cancer. This dataset depicts the proteomic changes observed in C57BL/6J mice expressing wild-type or 3SA-phospho mutant versions of the Bcl-2-associated death promoter, BAD. This data shows that BAD regulates postnatal mammary gland morphogenesis in puberty. Three conserved serine residues on BAD are co-ordinately phosphorylated to regulate its activity. Non-phosphorylated BAD mutant delayed pubertal ductal elongation. This defect was specific to the epithelial compartment as transplant and ex vivo organoid assays of mutant epithelium recapitulated decreased tubule migration. Proteomic signature between BAD+/+ and phosphomutant BAD-3SA mammary glands identified differences in actin-binding and focal adhesion components. Mechanistically, non-phosphorylated BAD impedes protein translation, specifically in protrusions, through aberrant hypophosphorylated 4E-BP1. These findings reveal a critical enhancement of localized translation for efficient pubertal-mammary-gland morphogenesis and identifies BAD as a novel regulator of this process.
2021-03-29 | PXD014347 | Pride
Project description:Purpose: discover the downstream pathways and the mechanism of target activation by the p53:Myc axis in normal mammary and cancer stem cells Methods: we performed ChIPseq experiments from NMuMG cells grown in adhesion under standard conditions Results: the p53:Myc axis orchestrates its transcriptional response in mammary-epithelial cells via a dual and overlapping mechanism: i) a tightly controlled epistasis driven by p53 and executed by Myc, and ii) a co-operative double occupancy of their downstream effectors at different regulatory regions
2019-01-21 | GSE87002 | GEO
Project description:Upon induction, WAP-T mice express two synergistically acting SV40 early region encoded proteins, large (LT) and small (sT) tumor antigens in the mammary epithelium, recapitulating thereby the loss of p53 and Rb function and deregulation of PP2A-controlled mitogenic pathways in human breast cancer. In primiparous mice, WAP-promoter driven expression of SV40 proteins induces well and poorly differentiated (respectively low- and high-grade) mammary adenocarcinomas. We here studied the postulated mutant p53 (mutp53) 'gain of function' during mammary tumor development, progression and metastasis by crossing WAP-T mice with mutant p53 transgenic WAP-mutp53 mice.
2013-12-18 | GSE53395 | GEO
Project description:We compared the expression levels of X-linked genes in the mammary glands of Brca1 D11/D11;p53+/- mutant and control (p53+/-) mice at three different stages of the mammary cycle: virgin, pregnant day 16.5, and lactation day 1, using a cDNA microarray. In about 690 X-linked genes that are expressed at these three stages of mammary cycle of development, we found 16 X-linked genes showed altered expression levels in Brca1 D11/D11;p53+/- mammary glands in comparison with controls at all three time points. Among them, 9 genes were up-regulated and 7 were down-regulated. This result indicates that mutation of Brca1 could affect expression of a few X-linked genes in mammary tissues. However, this was unlikely caused by failure of X chromosome inactivation, as seven of them were down-regulated, and Xist RNA was expressed in all the Brca1 mutant mammary tissues. Keywords: BRCA1 mutation analysis
2006-09-19 | GSE5861 | GEO