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 (Strom, A., Arai, N., Leers, J., and Gustafsson, J. Angstrom. (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 a 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 a-positive breast cancer cell lines.