Opposite effects of estrogen receptors alpha and beta on MCF-7 sensitivity to the cytotoxic action of TNF and p53 activity

Oncogene. 2005 Jul 14;24(30):4789-98. doi: 10.1038/sj.onc.1208595.


We have investigated the effect of estrogen on p53 cellular location and its influence on tumor cell susceptibility to tumor necrosis factor (TNF)-mediated cytotoxic action. For this purpose, we have used the TNF-sensitive human breast adenocarcinoma MCF-7 and its derivative, the TNF-resistant 1001 clone. Our data indicate that although estrogen receptor (ER)alpha is present in both cell lines, estrogen treatment (1x10(-8) M) has an influence only on the MCF-7 cells and protects these cells from the TNF cytotoxicity. This protective effect is associated with translocation of p53 from the nucleus to the cytoplasm in p53 wild-type MCF-7 and not in p53-mutated 1001 cells. The translocation of p53 in MCF-7 cells results in a decrease in its transcriptional activity, as revealed by diminished p21(WAF1/CIP1) induction and an altered ratio of Bax and Bcl-2 proteins. The estrogen-induced effects are reversed by the selective estrogen inhibitor 182, 780 (1x10(-6) M). Interestingly, transient transfection of MCF-7 cells with ERbeta but not ERalpha cDNA encoding plasmid results in retention of p53 in the nucleus, a subsequent potentiation of its transcriptional activity, and in an increased MCF-7 sensitivity to TNF. The estrogen effects on p53 location and transcriptional activity may involve the mdm2 protein since both events were reversed following MCF-7 transfection with plasmid encoding the ARF cDNA. These studies suggest that estrogen-induced MCF-7 cell survival in the presence of TNF requires a transcriptionally active p53 and, more importantly, indicate that introduction of ERbeta can attenuate the estrogen effects on the p53 protein location, its transcriptional activity and also results in a potentiation of cell sensitivity to TNF-mediated cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism*
  • Estrogens / pharmacology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Nuclear Proteins / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Transcription, Genetic / genetics
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors / toxicity*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*


  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2