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Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [CGH data]

ABSTRACT: The retinoblastoma (RB) and p53 tumor suppressors are critical regulators of the cell cycle with profound impact on both normal cell biology and disease etiology. In the context of human cancers, compound inactivation of RB and p53 is a frequent occurrence; however, the cooperation of these tumor suppressors in driving tumorigenesis has proven to be intricate and dependent on both the tissue and type of cancer. Hepatocellular carcinoma (HCC) is a highly complex disease characterized by numerous molecular abnormalities (e.g. p53, RB, TGFβ) and chromosomal aberrations associated with environmental factors (e.g. Hepatitis B/C Virus, Aflatoxin B1). Despite extensive research, how each of these facets of disease development cooperates in promoting tumorigenesis is ultimately unknown. In the current study, we present a mouse model of liver tumorigenesis, in which the impact of RB and p53 loss is modified by the tissue environment. While loss of RB and p53 promotes deregulation of transcriptional programs associated with advanced disease, these changes are not sufficient to drive spontaneous tumorigenesis in the liver. However, in response to carcinogen-induced damage, distinct and cooperative roles of RB and p53 are revealed, which critically impact cell cycle control, checkpoint response, genome stability, and ultimately tumor development.

ORGANISM(S): Mus musculus

PROVIDER: GSE29847 | GEO | 2011/09/20

SECONDARY ACCESSION(S): PRJNA141011

REPOSITORIES: GEO

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Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [expression data]

2011-09-20 | GSE29846 | GEO

Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [CGH data]

Project description:The retinoblastoma (RB) and p53 tumor suppressors are critical regulators of the cell cycle with profound impact on both normal cell biology and disease etiology. In the context of human cancers, compound inactivation of RB and p53 is a frequent occurrence; however, the cooperation of these tumor suppressors in driving tumorigenesis has proven to be intricate and dependent on both the tissue and type of cancer. Hepatocellular carcinoma (HCC) is a highly complex disease characterized by numerous molecular abnormalities (e.g. p53, RB, TGFβ) and chromosomal aberrations associated with environmental factors (e.g. Hepatitis B/C Virus, Aflatoxin B1). Despite extensive research, how each of these facets of disease development cooperates in promoting tumorigenesis is ultimately unknown. In the current study, we present a mouse model of liver tumorigenesis, in which the impact of RB and p53 loss is modified by the tissue environment. While loss of RB and p53 promotes deregulation of transcriptional programs associated with advanced disease, these changes are not sufficient to drive spontaneous tumorigenesis in the liver. However, in response to carcinogen-induced damage, distinct and cooperative roles of RB and p53 are revealed, which critically impact cell cycle control, checkpoint response, genome stability, and ultimately tumor development. Mice that are transgenic for Cre recombinase under the albumin promoter and harboring loxP sites within the Rb and/or p53 genes. For gene expression microarray analysis, mice were aged to 14 days, and treated for 24 hours with diethylnitrosamine (DEN) or saline as a control. For CGH analysis, mice were aged to 6 months post-DEN treatment. Liver tissue was obtained from dissected tumors and compared to normal liver tissue of 6-month old, saline-treated littermates. CGH analysis includes 5 individual tumor samples and 2 control samples (each consisting of a pool of 3 normal mouse liver DNA).

2011-09-19 | E-GEOD-29847 | biostudies-arrayexpress

Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [expression data]

2011-09-19 | E-GEOD-29846 | biostudies-arrayexpress

aCGH data of Rb/p53 deficient mammary tumors

Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used aCGH to detect copy number alterations associated with Rb/p53 deletion. Tumor DNAs from MMTV-Cre: Rbf/f;p53f/f and Ad-Cre: Rbf/f;p53f/f conditional mutant mice are being compared to pooled tail DNAs in order to identify common alterations associated with Rb/p53 deficient tumorigenesis

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RB pathway deregulation promotes invasion and disease progression in a mouse model of MYC-overexpressing mammary tumorigenesis

Project description:Breast cancer is a highly heterogeneous disease that is categorized into distinct tumor subtypes based on specific molecular attributes, which ultimately influence therapeutic options. Unlike ER+ and/or HER2+ cancers that are subject to specific targeted therapies, triple negative breast cancers (TNBCs) do not express these receptors, which leaves patients with limited treatment options. Thus, significant focus has been placed on identifying molecular attributes of basal-like disease that could be used to develop and/or direct novel treatment regimens. Activation of MYC signaling and inactivation of the RB-pathway are frequent events in many types of human cancers. These pathways influence many biological processes, such as cell proliferation, that contribute to the aggressiveness and therapeutic response of tumors. The current study examines the interaction of the MYC and RB pathways in mammary epithelial cell tumorigenesis. Mouse mammary epithelial cells were isolated and sub-cultured. Adenoviral expression of Cre-recombinase was used to delete the RB and/or p53 genes, and retrovirus was used to achieve MYC overexpression (OE). Proliferating cells were harvested for each condition, and RNA was isolated for analyses.

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Expression data from mouse adult fibroblasts with Rb deletion and/or p53DD expression exposed to cisplatin (CDDP)

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Expression data from mouse adult fibroblasts with Rb deletion and/or p53DD expression exposed to cisplatin (CDDP)

Project description:The RB and p53 tumor suppressor pathways regulate the transcription of genes involved in cell cycle progression, DNA replication, DNA repair, and apoptosis. These tumor suppressors are critical modulators of the response to genotoxic damage and both pathways are frequently inactivated in human cancers. We used microarrays to monitor gene expression patterns upon exposure to cisplatin treatment in fibroblasts harboring loss/inactivation of RB and/or p53. We generated mouse adult fibroblasts harboring loss/inactivation of RB and/or p53 and subjected these cell populations to cisplatin treatment for 24 hours. Treated cell populations were allowed to recover from cisplatin exposure, generating a recurred cell popuation. Untreated and recurred cell populations were then subjected to RNA extraction and hybridization on Affymetrix microarrays.

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Expression data comparing Rb/p53 and p53 deficient mammary tumors and normal mammary tissue

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2014-10-03 | E-GEOD-62016 | biostudies-arrayexpress

Expression data comparing Rb/p53 and p53 deficient mammary tumors and normal mammary tissue

Project description:To investigate the impact of combined Rb and p53 loss in mammary tumorigenesis, we used transgenic and viral approaches to delete Rb and p53 floxed alleles specifically in the mouse mammary epithelium. Although MMTV-Cre (NLST) targets stem/bi-potent progenitors in the mammary gland, a subset of MMTV-Cre:Rbf/f;p53f/f mice developed non-mammary tumors. Thus, freshly isolated primary mammary epithelial cells from these animals were transplanted into the mammary fat pads of immunodeficient mice and monitored for tumor formation. In addition, primary MECs were isolated from Cre-negative Rbf/f;p53f/f mice, infected with Ad-Cre followed by orthotopic transplantation. In all these cases, resulting tumors shared similar spindle-shape histology, expressed high levels of vimentin, a mesenchymal marker, but not E-cadherin, a luminal marker, and were classified as adeno-sacrcomatoid/spindle-cell/mesenchymal-like breast cancer. We used microarrays to detect differentially expressed genes in the Rb/p53 double-knock-out vs p53 single deletion or normal mammary tissue.

2014-10-03 | GSE62016 | GEO

Gene expression profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment

Project description:This SuperSeries is composed of the following subset Series: GSE29846: Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [expression data] GSE29847: Genomic profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment [CGH data] Refer to individual Series

2011-09-19 | E-GEOD-24347 | biostudies-arrayexpress

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