Mitogenic Estrogen Metabolites Alter the Expression of β-estradiol-regulated Proteins Including Heat Shock Proteins in Human MCF-7 Breast Cancer Cells

  • Kim, Seong Hwan (Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology) ;
  • Lee, Su-Ui (Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology) ;
  • Kim, Myung Hee (Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology) ;
  • Kim, Bum Tae (Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology) ;
  • Min, Yong Ki (Laboratory of Chemical Genomics, Bio-Organic Science Division, Korea Research Institute of Chemical Technology)
  • Received : 2005.07.12
  • Accepted : 2005.08.30
  • Published : 2005.12.31

Abstract

Estrogen metabolites are carcinogenic. The comparative mitogenic activities of $17{\beta}$-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), $16{\alpha}$-hydroxyestrone ($16{\alpha}$-OHE1) and 2-methoxyestradiol (2-ME), were determined in estrogen receptor(ER)-positive MCF-7 human breast cancer cells. Each of the E2 metabolites caused proliferation of the MCF-7 cells, but only E2 and $16{\alpha}$-OHE1 induced a greater than 20-fold increases in transcripts of the progesterone receptor (PR) gene, a classical ER-mediated gene. This suggests that the mitogenic action of E2 and $16{\alpha}$-OHE1 could result from their effects on gene expression via the ER. E2 metabolites altered the expression of E2-regulated proteins including heat shock proteins (Hsps). $16{\alpha}$-OHE1 and 2-ME as well as E2 increased levels of Hsp56, Hsp60, $Hsp90{\alpha}$ and Hsp110 transcripts, and the patterns of these inductions resembled that of PR. Hsp56 and Hsp60 protein levels were increased by all the E2 metabolites. Levels of the transcripts of 3 E2-upregulated proteins (XTP3-transactivated protein A, protein disulfide isomerase-associated 4 protein and stathmin 1) and an E2-downregulated protein (aminoacylase 1) were also affected by the E2 metabolites. These results suggest that the altered expression of Hsps (especially Hsp56 and Hsp60) by E2 metabolites such as E2, $16{\alpha}$-OHE1 and 2-ME could be closely linked to their mitogenic action.

Keywords

2-Hydroxyestradiol;2-Methoxyestradiol;4-Hydroxyestradiol;$16{\alpha}$-Hydroxyestrone;$17{\beta}$-Estradiol;Breast Cancer;Heat Shock Proteins

Acknowledgement

Grant : Chemical Genomics Research Project

Supported by : MOST (Ministry of Science and Technology), Korea Research Institute of Chemical Technology

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