ΔTAp73 upregulation correlates with poor prognosis in human tumors:: Putative in vivo network involving p73 isoforms, p53, and E2F-1

Purpose Although full-length TAp73 variants largely mimic p53 suppressor activities, the transactivation-deficient transcripts Delta TAp73 exert an oncogenic effect by inactivating p53 and TAp73 suppressor properties. Additionally, Delta TAp73 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 Delta TAp73 variants and assess possible associations with E2F-7, p53 and K-ras status. We address the possible clinical relevance of alterations in these genes. Patients and Methods We determine in 113 colon and 60 breast cancer patients (a) the expression levels of TAp73, Delta TAp73 (Delta Ex2p73, Delta Ex2/3p73, and Delta Np73), 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 Delta TAp73 variants and advanced pathologic stage, lymph node metastasis, vascular invasion, presence of polyps, and tumor localization. Conclusion Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of Delta TAp73 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.