Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.
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2016 Jul 1;9(7):749-57. doi: 10.1242/dmm.025239. Epub
2016 May 5.Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers.1, 2, 3, 3, 4, 3, 5, 6.1Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.2Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.3The McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO 63108, USA.4Department of Biomedical Sciences, University at Albany, Rensselaer, NY 12144, USA.5Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.6Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA cperou@med.unc.edu.AbstractTargeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3 As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways. (C) 2016. Published by The Company of Biologists Ltd.KEYWORDS: Basal- E Genetically eng P Whole- p53PMID:
[PubMed - in process] Human counterparts of Trp53-null transplant tumors. (A) Genes highly expressed within each Trp53-null transplant class were identified using a two-class (class x versus all others) SAM analysis (FDR 0%) across our 385-sample murine microarray dataset. The standardized average of these gene signatures was calculated across more than 3000 human tumors and displayed by intrinsic subtype. (B) Tumor differentiation scores (D-Scores) () were calculated for all 385 murine samples and displayed by intrinsic class. The D-Scores of the three Trp53-null transplant classes were compared using a Student's t-test.Dis Model Mech. 2016 July 1;9(7):749-757.Murine Trp53-null tumor datasets. Sequencing and microarray technologies were used to produce four Trp53-null tumor datasets of varying sizes: (i) whole genome sequencing (n=12), (ii) exome sequencing (n=25), (iii) DNA copy-number microarray (n=43) and (iv) gene expression microarray (n=43). The intrinsic class of each sample is displayed on the dendrogram, with colored boxes being previously identified human subtype counterparts (). The hierarchical clustering location of each p53-null tumor within the datasets is displayed as a vertical black strip. *The Trp53-null transplant model produces heterogeneous tumors that primarily develop into one of these three murine expression subtypes. For each dataset, the number of tumors studied from each of the three murine classes highlighted by ‘*’ is displayed on the right-hand side of the figure.Dis Model Mech. 2016 July 1;9(7):749-757.Chromosome structural-variation analysis. Displayed are circos plots of the structural variants (SVs) enriched within (A) p53null-BasalEx, (B) p53null-Claudin-lowEx and (C) p53null-LuminalEx tumors as determined by a two-class (class x versus all others) Fisher's exact test. The genes affected by these SVs are listed under each circos plot.Dis Model Mech. 2016 July 1;9(7):749-757.DNA copy-number analysis. Displayed in genomic order are the median class DNA copy-number levels for (A) p53null-BasalEx, (B) p53null-Claudin-lowEx and (C) p53null-LuminalEx tumors. DNA copy-number changes enriched within each of the three Trp53-null transplant classes were identified using a two-class (class x versus all others) SAM analysis. Genomic regions of significant gain are labeled in red and regions of significant loss are labeled in green.Dis Model Mech. 2016 July 1;9(7):749-757.Conserved DNA aberrations with human basal-like tumors. Pearson correlations between DNA copy number and gene expression were determined for all genes within the significant regions of gain and loss from . Genes with a correlation greater than or equal to 0.5 are displayed in genomic order. The heatmap corresponds to DNA copy-number abundance. The percentage of human non-basal and human basal-like tumors affected by amplification or deletion of these genes is displayed. Human basal-like enriched events (indicated by ***) were determined using a two-class Fisher's exact test (P&0.05). CL, p53null-Claudin-lowEx.Dis Model Mech. 2016 July 1;9(7):749-757.Candidate drug targets. (A) Candidate-drug-target filtering steps. (B) Final drug-target candidates for p53null-BasalEx and p53null-LuminalEx tumors. (C) Correlation of DNA and RNA for Met. (D) Change in tumor volume after 14 days of continuous crizotinib treatment displayed as box-and-whisker plots.Dis Model Mech. 2016 July 1;9(7):749-757.Grant SupportFull Text SourcesMiscellaneous
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External link. Please review our .Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II - Han - 2009 - Synapse -
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Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. Disturbed glutamate signaling resulting in hypofunction of N-methyl-D-aspartate receptors (NMDAR) has been implicated in the pathophysiology of schizophrenia. Glutamate Carboxypeptidase II (GCP II) hydrolyzes N-acetyl-alpha L-aspartyl-L-glutamate (NAAG) into glutamate and N-acetyl-aspartate. NAAG is a neuropeptide that is an NMDAR antagonist as well as an agonist for the metabotropic glutamate receptor-3 (mGluR3), which inhibits glutamate release. The aggregate effect of NAAG is thus to attenuate NMDAR activation. To manipulate the expression of GCP II, LoxP sites were inserted flanking exons 1 and 2, which were excised by crossing with a Cre-expressing mouse. The mice heterozygous for this deletion showed a 50% reduction in the expression level of protein and functional activity of GCP II in brain samples. Heterozygous mutant crosses did not yield any homozygous null animals at birth or as embryos (N & 200 live births and fetuses). These data are consistent with the previous report that GCP II homozygous mutant mice generated by removing exons 9 and 10 of GCP II gene were embryonically lethal and confirm our hypothesis that GCP II plays an essential role early in embryonic development. Heterozygous mice, however, developed normally to adulthood and exhibited increased locomotor activity, reduced social interaction, and a subtle cognitive deficit in working memory. Synapse 63:625&635, 2009. & 2009 Wiley-Liss, Inc.中兴pro的手机型号_百度知道
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