title: DeltaTAp73 upregulation correlates with poor prognosis in human tumors: putative in vivo network involving p73 isoforms, p53, and E2F-1.
abstract: OBJECTIVE
  Although full-length TAp73 variants largely mimic p53 suppressor activities, the transactivation-deficient transcripts DeltaTAp73 exert an oncogenic effect by inactivating p53 and TAp73 suppressor properties. Additionally, DeltaTAp73 may cooperate with oncogenic RAS to induce cell transformation, confer drug resistance, and induce the phosphorylation of phosphorylated Rb. Here, we study the expression of TAp73 and DeltaTAp73 variants and assess possible associations with E2F-1, p53 and K-ras status. We address the possible clinical relevance of alterations in these genes.
  
  
  METHODS
  We determine in 113 colon and 60 breast cancer patients (a) the expression levels of TAp73, DeltaTAp73 (DeltaEx2p73, DeltaEx2/3p73, and DeltaNp73), and E2F-1 transcripts by quantitative real-time reverse transcriptase polymerase chain reaction (PCR); (b) mutations in the first exon of K-ras by PCR-single-stranded confirmational polymorphism; and (c) p53 status by immunohistochemistry. Tumor characteristics were examined in each patient.
  
  
  RESULTS
  Both suppressor and oncogenic isoforms of TP73 were significantly coupregulated in tumor tissues. Associations were observed between (a) p53 wild type status and upregulation of some TP73 variants; (b) overexpression of E2F-1 and some TP73 forms; and (c) upregulation of DeltaTAp73 variants and advanced pathologic stage, lymph node metastasis, vascular invasion, presence of polyps, and tumor localization.
  
  
  CONCLUSIONS
  Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of DeltaTAp73 isoforms and poor prognosis features, specifically advanced tumor stage, suggests that they may be of practical clinical prognostic value. Interestingly, the in vivo associations identified here may indicate a functional network involving p73 variants, p53, and E2F-1.
authors.affiliation: Department of Medical Oncology, Hospital Universitario Puerta de Hierro, C/ San Martín de Porres, 4, 28035-Madrid, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Domínguez
authors.forename: José M
authors.initials: JM
authors.lastname: García
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.forename: Javier
authors.initials: J
authors.lastname: Silva
authors.forename: Vanesa
authors.initials: V
authors.lastname: García
authors.forename: Lara
authors.initials: L
authors.lastname: Martínez
authors.forename: Constanza
authors.initials: C
authors.lastname: Maximiano
authors.forename: María E
authors.initials: ME
authors.lastname: Gómez
authors.forename: José A
authors.initials: JA
authors.lastname: Rivera
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Andrade
authors.forename: Felix
authors.initials: F
authors.lastname: Bonilla
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011379:Prognosis; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D009687:Nuclear Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human