The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression

J Biol Chem. 2002 Aug 9;277(32):28376-9. doi: 10.1074/jbc.C200340200. Epub 2002 Jun 21.

Abstract

All-trans-retinoic acid has been shown to have an antiproliferative effect in the estrogen receptor alpha-positive breast cancer cell line MCF-7. The mechanism of this effect is not well understood. We have previously shown that 17beta-estradiol down-regulates the basic helix-loop-helix factor Hairy and Enhancer of Split homologue-1 in MCF-7 and T47D cells (Ström, A., Arai, N., Leers, J., and Gustafsson, J. A. (2000) Oncogene 19, 5951-5953) and that this down-regulation is essential for proliferation in response to 17beta-estradiol. Treatment of the same cells with all-trans-retinoic acid prevented 17beta-estradiol-mediated down-regulation of the factor. The antiproliferative effect of all-trans-retinoic acid correlated well with the prevention of Hairy and Enhancer of Split homologue-1 down-regulation. Increasing concentrations of all-trans-retinoic acid, in the range of 1-1000 nm, produced a dose-dependent inhibition of proliferation and prevented 17beta-estradiol-mediated down-regulation of Hairy and Enhancer of Split homologue-1. By using a receptor-specific ligand we were able to show that the retinoic acid receptor alpha is important for regulation of the Hairy and Enhancer of Split homologue-1. Expression of a dominant negative form of Hairy and Enhancer of Split homologue-1 in MCF-7 cells abolished the growth-inhibitory effect of all-trans-retinoic acid in these cells. This finding indicates that Hairy and Enhancer of Split homologue-1 is a mediator of the antiproliferative effect of all-trans-retinoic acid in estrogen receptor alpha-positive breast cancer cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • COS Cells
  • Cell Division
  • Cell Line
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Estradiol / metabolism
  • Genes, Dominant
  • Homeodomain Proteins / biosynthesis*
  • Humans
  • Precipitin Tests
  • RNA, Messenger / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor HES-1
  • Transcription, Genetic
  • Transfection
  • Tretinoin / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • RARA protein, human
  • RNA, Messenger
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Transcription Factor HES-1
  • HES1 protein, human
  • Estradiol
  • Tretinoin