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  • Title: The N-terminal of the estrogen receptor (ERalpha) mediates transcriptional cross-talk with the retinoic acid receptor in human breast cancer cells.
    Author: Rousseau C, Pettersson F, Couture MC, Paquin A, Galipeau J, Mader S, Miller WH.
    Journal: J Steroid Biochem Mol Biol; 2003 Jul; 86(1):1-14. PubMed ID: 12943740.
    Abstract:
    Transcriptional cross-talk exists between the estrogen receptor (ERalpha) and retinoic acid receptor (RAR) pathways in human breast cancer cells. We have previously shown that re-expression of ERalpha in ER-negative cells stimulates the transcriptional and growth inhibitory effects of all-trans-retinoic acid (tRA) by a mechanism that is independent of the ER ligands estradiol and tamoxifen. In this study, we generated cell lines stably expressing ERalpha-deletion mutants to elucidate the mechanism whereby ERalpha modulates RAR transcriptional activity. Using RT-PCR and RNAse protection assays, we observed that expression of ERalpha suppresses basal expression of the RA-responsive gene RARbeta2, while allowing it to be strongly induced by tRA. Repression of basal RARbeta2 transcription was confirmed by transient expression of the reporter plasmid betaRE-tk-CAT, containing the RARbeta2 promoter. In the ERalpha-negative cells, on the other hand, transcription was only weakly induced by RA. We further determined that this effect of ERalpha on RARbeta induction required the N-terminal AF-1-containing region, including the DNA-binding domain, but was independent of the C-terminal ligand-binding domain. Consistent with these results, the ER agonist estradiol and the AF-2 antagonist 4-hydroxytamoxifen had no significant effect on betaRARE activity. Conversely, the full ER antagonist ICI 182,780, which blocks ERalpha AF-1 activity, was able to completely relieve repression of basal betaRARE activity. The effect of ERalpha is specific for RAR-mediated transcription and does not occur on promoters containing typical response elements for the Vitamin D or thyroid hormone receptors. Moreover, the cross-talk between ERalpha and RAR does not seem to be mediated by sequestration of a number of common co-regulators, suggesting a novel mechanism whereby the N-terminal region of ERalpha modulates the transcriptional activity of RAR.
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