Transcription factor E2F-1 acts as a growth-promoting factor and is associated with adverse prognosis in non-small cell lung carcinomas

J Pathol. 2002 Oct;198(2):142-56. doi: 10.1002/path.1121.


Numerous upstream stimulatory and inhibitory signals converge to the pRb/E2F pathway, which governs cell-cycle progression, but the information concerning alterations of E2F-1 in primary malignancies is very limited. Several in vitro studies report that E2F-1 can act either as an oncoprotein or as a tumour suppressor protein. In view of this dichotomy in its functions and its critical role in cell cycle control, this study examined the following four aspects of E2F-1 in a panel of 87 non-small cell lung carcinomas (NSCLCs), previously analysed for defects in the pRb-p53-MDM2 network: firstly, the status of E2F-1 at the protein, mRNA and DNA levels; secondly, its relationship with the kinetic parameters and genomic instability of the tumours; thirdly, its association with the status of its transcriptional co-activator CBP, downstream target PCNA and main cell cycle regulatory and E2F-1-interacting molecules pRb, p53 and MDM2; and fourthly, its impact on clinical outcome. The protein levels of E2F-1 and its co-activator CBP were significantly higher in the tumour area than in the corresponding normal epithelium (p<0.001). E2F-1 overexpression was associated with increased E2F-1 mRNA levels in 82% of the cases examined. The latter finding, along with the low frequency of E2F-1 gene amplification observed (9%), suggests that the main mechanism of E2F-1 protein overexpression in NSCLCs is deregulation at the transcriptional level. Mutational analysis revealed only one sample with asomatic mutation at codon 371 (Glu-->Asp) and one carrying a polymorphism at codon 393 (Gly-->Ser). Carcinomas with increased E2F-1 positivity demonstrated a significant increase in their growth indexes (r=0.402, p=0.001) and were associated with adverse prognosis (p=0.033 by Cox regression analysis). The main determinant of the positive association with growth was the parallel increase between E2F-1 staining and proliferation (r=0.746, p<0.001), whereas apoptosis was not influenced by the status of E2F-1. Moreover, correlation with the status of the pRb-p53-MDM2 network showed that the cases with aberrant pRb expression displayed significantly higher E2F-1 indexes (p=0.033), while a similar association was noticed in the group of carcinomas with deregulation of the p53-MDM2 feedback loop. In conclusion, the results suggest that E2F-1 overexpression may contribute to the development of NSCLCs by promoting proliferation and provide evidence that this role is further enhanced in a genetic background with deregulated pRb-p53-MDM2 circuitry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • CREB-Binding Protein
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle Proteins / metabolism*
  • Cell Division
  • DNA Mutational Analysis
  • DNA, Complementary / analysis
  • DNA, Neoplasm / analysis
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Prognosis
  • Regression Analysis
  • Survival Rate
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Biomarkers, Tumor
  • Cell Cycle Proteins
  • DNA, Complementary
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • CREB-Binding Protein
  • CREBBP protein, human