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Breast Tumors with Elevated Expression of 1q Candidate Genes Confer Poor Clinical Outcome and Sensitivity to Ras/PI3K Inhibition
Saiharish A.V. Raghavan
Published in
2013
PMID: 24147022
Volume: 8
   
Issue: 10
Abstract
Genomic aberrations are common in cancers and the long arm of chromosome 1 is known for its frequent amplifications in breast cancer. However, the key candidate genes of 1q, and their contribution in breast cancer pathogenesis remain unexplored. We have analyzed the gene expression profiles of 1635 breast tumor samples using meta-analysis based approach and identified clinically significant candidates from chromosome 1q. Seven candidate genes including exonuclease 1 (EXO1) are consistently over expressed in breast tumors, specifically in high grade and aggressive breast tumors with poor clinical outcome. We derived a EXO1 co-expression module from the mRNA profiles of breast tumors which comprises 1q candidate genes and their co-expressed genes. By integrative functional genomics investigation, we identified the involvement of EGFR, RAS, PI3K/ AKT, MYC, E2F signaling in the regulation of these selected 1q genes in breast tumors and breast cancer cell lines. Expression of EXO1 module was found as indicative of elevated cell proliferation, genomic instability, activated RAS/AKT/MYC/E2F1 signaling pathways and loss of p53 activity in breast tumors. mRNA-drug connectivity analysis indicates inhibition of RAS/PI3K as a possible targeted therapeutic approach for the patients with activated EXO1 module in breast tumors. Thus, we identified seven 1q candidate genes strongly associated with the poor survival of breast cancer patients and identified the possibility of targeting them with EGFR/RAS/PI3K inhibitors. © 2013 Muthuswami et al.
About the journal
JournalPLoS ONE
ISSN19326203
Open AccessYes
Concepts (67)
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    EPIDERMAL GROWTH FACTOR RECEPTOR
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    Exonuclease
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    EXONUCLEASE 1
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    Messenger rna
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    Myc protein
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    PHOSPHATIDYLINOSITOL 3 KINASE
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    Protein kinase b
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    Protein p53
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    RAS PROTEIN
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    Transcription factor e2f
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    Unclassified drug
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    Article
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    Breast tumor
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    Cancer cell culture
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    Cancer grading
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    CANCER PATIENT
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    Cancer survival
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    Cell proliferation
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    CHROMOSOME 1
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    CHROMOSOME ABERRATION
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    Controlled study
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    Copy number variation
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    Enzyme activation
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    Enzyme inhibition
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    Functional genomics
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    Gene amplification
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    Gene expression
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    Gene expression profiling
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    GENE IDENTIFICATION
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    Gene locus
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    GENOMIC INSTABILITY
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    Human
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    Human cell
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    INTRADUCTAL CARCINOMA
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    Major clinical study
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    Open reading frame
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    Outcome assessment
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    Overall survival
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    Phenotype
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    Promoter region
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    Protein targeting
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    Real time polymerase chain reaction
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    RECURRENCE FREE SURVIVAL
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    Signal transduction
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    Tumor volume
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    Western blotting
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    Breast neoplasms
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    Cell line, tumor
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    CHROMONES
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    Chromosome mapping
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    CHROMOSOMES, HUMAN, PAIR 1
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    Cluster analysis
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    DNA REPAIR ENZYMES
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    Drug resistance, neoplasm
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    E2F TRANSCRIPTION FACTORS
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    EXODEOXYRIBONUCLEASES
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    Female
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    GENE EXPRESSION REGULATION, NEOPLASTIC
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    Gene regulatory networks
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    Humans
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    Morpholines
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    Neoplasm grading
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    PHOSPHATIDYLINOSITOL 3-KINASES
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    Proto-oncogene proteins c-myc
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    PROTO-ONCOGENE PROTEINS P21(RAS)
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    Quantitative trait loci
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    RECEPTOR, EPIDERMAL GROWTH FACTOR