Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy

Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1316-22. doi: 10.1016/j.ijrobp.2009.01.004. Epub 2009 Apr 11.

Abstract

Purpose: To examine the prognostic value of the 4E-BP1 activation state and related upstream/downstream signaling proteins on the clinical outcome of patients with intermediate- or high-risk early-stage cervical carcinoma treated with postoperative radiotherapy and to determine the optimal treatment of early-stage cervical carcinoma.

Methods and materials: Immunohistochemical staining was performed on 64 formalin-fixed, paraffin-embedded cervical carcinoma surgical specimens for each protein of the panel (p4E-BP1, phosphorylated mitogen-activated protein kinase, pAkt, vascular endothelial growth factor, KDR, Bcl-2, TP53, receptor for activated C-kinase 1). The expression patterns were related to the clinical data. All patients received postoperative radiotherapy. Concurrent chemotherapy was added if high-risk features were present. The median follow-up was 40 months.

Results: Of the 64 patients, 13 received concomitant chemotherapy. p4E-BP1 overexpression in moderate/high-risk early-stage cervical carcinoma correlated significantly with disease-free survival (hazard ratio, 4.39; p = .009) and overall survival (hazard ratio, 4.88; p = .005). Vascular endothelial growth factor, and its receptor KDR, had positive immunoreactivity in all tumor samples. No correlation with clinical outcome was found for the remaining proteins evaluated.

Conclusion: In this study, moderate/high-risk early-stage cervical carcinoma with low p4E-BP1 expression was highly curable with the current postoperative treatments. For tumors with p4E-BP1 overexpression, new investigational strategies are needed.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Analysis of Variance
  • Cell Cycle Proteins
  • Combined Modality Therapy / methods
  • DNA-Binding Proteins / metabolism
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Neoplasm Proteins / metabolism*
  • Neoplasm Recurrence, Local / mortality*
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Array Analysis / methods
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface / metabolism
  • Uterine Cervical Neoplasms / metabolism*
  • Uterine Cervical Neoplasms / mortality*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / therapy
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • EIF4EBP1 protein, human
  • Neoplasm Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors for Activated C Kinase
  • Receptors, Cell Surface
  • TP53TG1 protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factor Receptor-2
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1