Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA399096 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:microRNA-143/145 loss induces Ras-signaling and cooperates with Pten-deficiency to promote basal-like breast cancer
| PRJNA388650 | ENA
Project description:microRNA-143/145 loss induces Ras-signaling and cooperates with Pten-deficiency to promote basal-like breast cancer [gene expression]
| PRJNA388659 | ENA
Project description:The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce non-malignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse Pten in mammary epithelium are highly differentiated and lack transplantable tumor initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbour transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations and mutational landscape, as well as reduced expression of microRNA-143/145. Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable Pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR145-deficiency significantly correlated with elevated RAS pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/RAS pathway activation exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with miR-145 loss or high RAS-pathway activity in aggressive forms of breast cancer, and a need to identify and prioritize these tumors for aggressive therapy. Array CGH data comparing 2 types of Pten-deficient tumors (well and poorly differentiated) with other modles of mouse mammary tumors
2017-08-18 | GSE99495 | GEO
Project description:The tumor suppressor PTEN is frequently inactivated in breast and other cancers; yet, germ-line mutations in this gene induce non-malignant hamartomas, indicating dependency on additional cooperating events. Here we show that most tumors derived from conditional deletion of mouse Pten in mammary epithelium are highly differentiated and lack transplantable tumor initiating cells (TICs) capable of seeding new tumors following orthotopic injection of FACS-sorted or tumorsphere cells. A rare group of poorly differentiated tumors did harbour transplantable TICs. These transplantable tumors exhibited distinct molecular classification, signaling pathways, chromosomal aberrations and mutational landscape, as well as reduced expression of microRNA-143/145. Stable knockdown of miR-143/145 conferred tumorigenic potential upon poorly transplantable Pten-deficient tumor cells through a mechanism involving induction of RAS signaling, leading to increased sensitivity to MEK inhibition. In humans, miR145-deficiency significantly correlated with elevated RAS pathway activity in basal-like breast cancer, and patients with combined PTEN/miR-145 loss or PTEN-loss/RAS pathway activation exhibited poor clinical outcome. These results underscore a selective pressure for combined PTEN loss together with miR-145 loss or high RAS-pathway activity in aggressive forms of breast cancer, and a need to identify and prioritize these tumors for aggressive therapy. Expression data comparing 2 types of Pten-deficient tumors (spindle and poorly differentiated) with other models of mouse mammary tumors
2017-06-02 | GSE99493 | GEO
Project description:Ephexin1 cooperates with K-Ras to promote oncogenic Ras-driven tumorigenesis
| PRJNA619876 | ENA
Project description:A growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. In contrast to these studies, we found that depletion or forced expression of mir-143 and mir-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. Surprisingly, we observed that loss of mir-143~145 from the tumor microenvironment significantly reduced tumor burden, indicating a non-cell- autonomous role for these miRNAs in promoting tumorigenesis. By examining the expression patterns of different cell populations isolated in vivo from tumor-bearing lungs using an integrated computational approach, we identified a role for mir-145 in stimulating the proliferation of endothelial cells by downregulating an inhibitory kinase, Camk1d, which prevents mitotic entry. As a consequence, tumors in mir-143~145- deficient animals exhibited diminished hallmarks of neo-angiogenesis, increased apoptosis and their expansion appeared limited by the tumor’s ability to co-opt the alveolar vasculature. These findings show that expression of the mir-143~145 cluster in the tumor stroma promotes rather than suppresses tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics.
2016-05-21 | GSE71877 | GEO
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples
2012-05-29 | E-GEOD-28712 | biostudies-arrayexpress
Project description:In a series of mouse genetic studies, we concluded that miR-143/145 expression in intestinal subepithelial myofibroblasts (ISEMFs) promotes epithelial regeneration after DSS-mediated injury in the colon. This experiment aims to identify miR-143/145 target genes that are involved in this function. We generated primary ISEMFs from wildtype and miR-143/145 null mouse colons and analyzed their gene expression profile. We further subjected ISEMFs to LPS treatment, in order to measure gene expression changes that are only revealed after inflammatory stress.
2014-05-22 | GSE55651 | GEO
Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.
2020-10-15 | PXD016184 | Pride
Project description:In a series of mouse genetic studies, we concluded that miR-143/145 expression in intestinal subepithelial myofibroblasts (ISEMFs) promotes epithelial regeneration after DSS-mediated injury in the colon. This experiment aims to identify miR-143/145 target genes that are involved in this function. We generated primary ISEMFs from wildtype and miR-143/145 null mouse colons and analyzed their gene expression profile. We further subjected ISEMFs to LPS treatment, in order to measure gene expression changes that are only revealed after inflammatory stress. Three wild-type and three miR-143/145 null ISEMF cell lines were isolated from mouse colons. Cells were treated with or without 1 ug/mL LPS for 24 hours and total RNA was isolated. Gene expression was profiled using Illumina microarrays.
2014-05-22 | E-GEOD-55651 | biostudies-arrayexpress