A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells

J Biol Chem. 2005 Apr 29;280(17):17480-7. doi: 10.1074/jbc.M501261200. Epub 2005 Feb 22.

Abstract

The expression of progesterone receptor (PR) is normally estrogen-dependent, and progesterone is only active in target cells following estrogen exposure. This study revealed that the effect of estrogen was markedly disrupted by estrogen-independent expression of PR. Transfection of PR in estrogen receptor (ER)-positive MCF-7 cells abolished the estradiol-17beta growth stimulatory effect that was observed in the parental cells and the vector-transfected controls in a ligand-independent manner. The antiestrogenic effect was also observed at the level of gene transcription. Estradiol-17beta (E2)-induced gene expression of pS2 and GREB1 was impaired by 50-75% after 24-72 h of E2 treatment in PR-transfected cells. Promoter interference assay revealed that PR transfection drastically inhibited E2-mediated ER binding to estrogen response elements (ERE). The antiestrogenic effects of transfected PR are associated with enhanced metabolism of E2. HPLC analysis of [3H]E2 in the samples indicated that the percentage of [3H]E2 metabolized by PR-transfected cells in 6 h is similar to that by vector-transfected control cells in 24 h (77 and 80%, respectively). The increased metabolism of E2 may, in turn, be caused by increased cellular uptake of E2, as demonstrated by whole cell binding of [3H]E2. The findings open up a new window for a hitherto unknown functional relationship between the PR and ER. The antiestrogenic effect of transfected PR also provides a potential therapeutic strategy for estrogen-dependent breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Breast Neoplasms / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatography, High Pressure Liquid
  • Estradiol / metabolism
  • Estrogen Receptor Modulators / metabolism*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / metabolism
  • Gene Expression Regulation
  • Humans
  • Promoter Regions, Genetic
  • Receptors, Progesterone / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcription, Genetic
  • Transfection

Substances

  • Estrogen Receptor Modulators
  • Estrogen Receptor alpha
  • Estrogens
  • Receptors, Progesterone
  • Estradiol