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Gene expression profiling of preneoplastic Lgr5-creERT2/PIK3CAH1047R mammary subsets

ABSTRACT: This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice

ORGANISM(S): Mus musculus

PROVIDER: GSE59870 | GEO | 2015/08/12

SECONDARY ACCESSION(S): PRJNA256956

REPOSITORIES: GEO

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Gene expression profiling of preneoplastic Lgr5-creERT2/PIK3CAH1047R mammary subsets

Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice Mammary cell subpopulations were isolated from Lgr5-creERT2/PIK3CA H1047R and Lgr5-creERT2 control animals 4 weeks after activation of PIK3CA H1047R transgene expression by Tamoxifen injection. Pooled mammary glands of 2-3 estrus-synchronized mice per genotype were sorted in 3 independent sortings and used for microarray analysis (24 samples in total).

2015-08-12 | E-GEOD-59870 | biostudies-arrayexpress

Gene expression profiling of preneoplastic K8-creERT2/PIK3CAH1047R mammary subsets

Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from K8-creERT2/PIK3CA H1047R mice Mammary cell subpopulations were isolated from K8-creERT2/PIK3CAH1047R and K8-creERT2 control animals 4 weeks after activation of PIK3CA H1047R transgene expression by Tamoxifen injection. Pooled mammary glands of 2-3 estrus-synchronized mice per genotype were sorted in 3 independent sortings and used for microarray analysis (20 samples in total).

2015-08-12 | E-GEOD-65411 | biostudies-arrayexpress

Gene expression profiling of preneoplastic K8-creERT2/PIK3CAH1047R mammary subsets

Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from K8-creERT2/PIK3CA H1047R mice

2015-08-12 | GSE65411 | GEO

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Project description:Gene expression profiling of preneoplastic Lgr5-creERT2/PIK3CAH1047R mammary subsets

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Project description:Gene expression profiling of Lgr5-creERT2/PIK3CA H1047R and K8-creERT2/PIK3CA H1047R-evoked mammary tumors

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High-dose oncogenic PIK3CA drives constitutive cellular stemness through increased NODAL/TGFb signaling

Project description:Oncogenic PIK3CA mutations activate phosphoinositide 3-kinase (PI3K) and are among the commonest somatic mutations in cancer and mosaic, developmental overgrowth disorders. We recently demonstrated that the ‘hotspot’ variant PIK3CAH1047R exerts striking allele dose-dependent effects on stemness in human induced pluripotent stem cells (iPSCs), and moreover demonstrated multiple oncogenic PIK3CA copies in a substantial subset of human cancers. To identify the molecular mechanism underpinning PIK3CAH1047R allele dose-dependent stemness, we profiled isogenic wild-type, PIK3CAWT/H1047R and PIK3CAH1047R/H1047R iPSCs by high-depth transcriptomics, proteomics and reverse-phase protein arrays (RPPA). PIK3CAH1047R/H1047R iPSCs exhibited altered expression of 5644 genes and 248 proteins, whereas heterozygous hPSCs showed 492 and 54 differentially-expressed genes and proteins, respectively, confirming a nearly deterministic phenotypic effect of homozygosity for PIK3CAH1047R. Pathway and network-based analyses predicted a strong association between self-sustained TGFb/NODAL signaling and the ‘locked’ stemness phenotype induced by homozygosity for PIK3CAH1047R. This stemness gene signature was maintained without exogenous NODAL in PIK3CAH1047R/H1047R iPSCs and was reversed by pharmacological inhibition of TGFb/NODAL signaling but not by PIK3CA-specific inhibition. Analysis of PIK3CA-associated human breast cancers revealed increased expression of the stemness markers NODAL and POU5F1 as a function of disease stage and PIK3CAH1047R allele dosage. Together with emerging realization of the link between NODAL re-expression and aggressive cancer behavior, our data suggest that TGFb/NODAL inhibitors warrant testing in advanced breast tumors with multiple oncogenic PIK3CA copies.

2021-03-03 | PXD014719 | Pride

PIK3CA-dependent hepatocarcinogenesis. A microarray comparing PIK3CA E545K and H1047R injected mice compared to age matched controls.

Project description:Gene expression microarray analyses of PIK3CA H1047R and E545K induced preneoplastic lesions and tumors compared to age matched controls. Plasmids expressing oncogenic forms of PIK3CA (H1047R or E545K mutants) were delivered to the mouse liver by tail vein hydrodynamic injection combined with Sleeping Beauty–mediated somatic integration (SBT-HTVI). Resulting preneoplastic and neoplastic lesions were subjected to gene expression microarray analysis. The putative PIK3CA target gene Galectin1 (Gal1) was further characterized by in vitro studies. Transfection of either PIK3CA E545K or H1047R mutants via SBT-HTVI was sufficient to induce hepatocellular carcinomas in mice. A stepwise hepatocarcinogenesis from singular pericentral lipid-rich preneoplastic hepatocytes to clusters, expansive preneoplastic lesions, and HCCs was observed. In PIK3CA H1047R injected mice, HCCs were detected in the 12 months injection group, while PIK3CA E545K injections resulted in tumor occurrence as early as 3 months after SB-HTVI. Histologically, a predominant lipid-rich phenotype characterized all tumorigenesis stages, as confirmed by Sudan III staining and electron microscopy. Immunohistochemically, preneoplastic lesions and tumors displayed high levels of the lipid master regulators Fatty acid synthase and Stearoyl-CoA desaturase-1. Gal1 was commonly overexpressed in PIK3CA-driven preneoplastic and neoplastic liver lesions by gene expression microarray analysis compared with age-matched controls.

2021-05-06 | GSE173963 | GEO

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Project description:Gene expression profiling of preneoplastic K8-creERT2/PIK3CAH1047R mammary subsets

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Gene expression profiling of Lgr5-creERT2/PIK3CA H1047R and K8-creERT2/PIK3CA H1047R-evoked mammary tumors

Project description:This study examined the gene expression profile of mammary tumors derived from Lgr5- and K8-positive cell-of-origins Mammary tumors and reference mammary glands from control mice were collected, cryo-homogenized, total RNA was isolated and analyzed by microarray (total 25 samples).

2015-08-12 | E-GEOD-59872 | biostudies-arrayexpress

Gene expression profiling of Lgr5-creERT2/PIK3CA H1047R and K8-creERT2/PIK3CA H1047R-evoked mammary tumors

Project description:This study examined the gene expression profile of mammary tumors derived from Lgr5- and K8-positive cell-of-origins

2015-08-12 | GSE59872 | GEO