The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression.
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.
Muller
Patrick
P
Center for Biotechnology, Karolinska Institute, Novum, S-141 57 Huddinge, Sweden.
Kietz
Silke
S
Gustafsson
Jan-Ake
JA
Strom
Anders
A
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D019556:COS Cells; D002455:Cell Division; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004958:Estradiol; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D000072056:Transcription Factor HES-1; D014212:Tretinoin; C000607071:RARA protein, human; C078493:HES1 protein, human