Gene expression profiles of mouse liver tissue harboring deletion of RB and/or p53, untreated or post-hepatocarcinogen treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Adam Ertel
PROVIDER: E-GEOD-24347 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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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
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-29846 | biostudies-arrayexpress
Project description:The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. In vitro and in vivo analyses demonstrated that LXCXE-binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE-binding is essential for exerting control over E2F3 and suppressing cell cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealed a requirement for LXCXE-binding in suppression of genotoxin-initiated hepatocellular carcinoma in vivo. Together, these studies establish an essential role of the LXCXE-binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression. Mice transgenic for Cre-recombinase under the albumin promoter contain indicated combinations of loxP sites flanking exon 19 of Rb1 (f), N750F mutation (NF) or wild-type (plus) genotypes. For gene expression microarray analysis, mice were aged to 14 days and treated for 24 hours with diethylnitrosamine (DEN) or saline as an M-bM-^@M-^\untreatedM-bM-^@M-^] control. Liver tissue was obtained from DEN treated livers and compared to normal liver tissue of saline treated littermates.
2011-12-01 | E-GEOD-31169 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by a pro-mutagenic chemical N-nitrosodiethylamine in presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor and non-tumor cirrhotic tissues). In addition, we compared our findings to those in human HCC (tumor and non-tumor cirrhotic/fibrotic tissues). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. When compared to CNAs in human HCC, we found that 33% of genes in these segments are similarly affected in the mouse tumors. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. Genomic DNA was extracted from frozen liver samples from vehicle-control and DEN+CCl4-treated mice using a DNEasy kit (Qiagen, Valencia, CA). Eighteen mouse tumor samples were included in the study, as well as 18 matched non-tumor samples taken from fibrotic, non-tumorous, surrounding liver tissue from the same mice. Liver DNA from 6 vehicle control-mice was pooled and used as the reference genome in the aCGH experiments. Copy number alterations were identified using the normalized data.
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Project description:The retinoblastoma tumor suppressor, Rb, is implicated in luminal-B and basal-like breast carcinomas, yet its effect on mammary gland development and causal role in breast cancer subtypes remain undefined. Here we show that conditional deletion of Rb in mouse mammary epithelium led to expansion of the stem/progenitor cells and to focal acinar hyperplasia with squamous metaplasia. These uniform lesions progressed into histologically diverse, transplantable mammary adenocarcinomas and adenosquamous carcinomas with features of luminal-B or basal-like carcinomas. A subset of basal-like but none of the luminal-B tumors expressed mutant p53. These results demonstrate a causative role for Rb in the etiology of breast cancer subtypes and implicate p53 status as a determinant of tumor phenotype after Rb loss. Keywords: reference x sample Will be updated soon
2010-07-06 | E-GEOD-14457 | biostudies-arrayexpress
Project description:To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in association with other proteins to form modules localized in particular subcellular compartments in specialized cell types and tissues. Sub-cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells. Here, we describe a strategy for tissue-biomarker detection based on a mitochondrial fold enrichment (mtFE) score, which is sensitive to protein abundance changes as well as changes in subcellular distribution between mitochondria and cytosol. The mtFE score integrates protein abundance data from total cellular lysates and mitochondria-enriched fractions, and provides novel information for the classification of cancer samples that is not necessarily apparent from conventional abundance measurements alone. We apply this new strategy to a panel of wild-type and mutant mice with a liver-specific gene deletion of Liver receptor homolog 1 (Lrh-1hep-/-), with both lines containing control individuals as well as individuals with liver cancer induced by diethylnitrosamine (DEN). Lrh-1 gene deletion attenuates cancer cell metabolism in hepatocytes through mitochondrial glutamine processing. We show that proteome changes based on mtFE scores outperform protein abundance measurements in discriminating DEN-induced liver cancer from healthy liver tissue, and are uniquely robust against genetic perturbation. We validate the capacity of selected proteins with informative mtFE scores to indicate hepatic malignant changes in two independent mouse models of hepatocellular carcinoma (HCC), thus demonstrating the robustness of this new approach to biomarker research.
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Project description:To date, most proteomic analyses towards cancer biomarker discovery have been based on protein quantification. However, proteins function in association with other proteins to form modules that are localized in specific subcellular compartments. Cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells1,2. Here, we describe a strategy for biomarker detection based on a mitochrondrial enrichment score (mtES), which is sensitive to protein abundance as well as protein translocation between mitochondria and cytosol. The mtES score integrates protein expression data from total cellular lysates and enriched mitochondrial fractions and provides important information for the classification of cancer samples, which is not apparent from conventional quantitative protein measurements. We apply the new strategy to a panel of wild-type and mutant mice that are either healthy or present liver cancer. We show that proteome changes based on mtES scores outperform protein abundance measurements in discriminating liver cancer from healthy liver tissue and that they are uniquely robust against strong genetic perturbation. Overall, our method provides a more sensitive approach to cancer biomarker discovery that takes into account contextual information of tested proteins.
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