Action of retinoic acid receptor on EGFR gene transactivation and breast cancer cell proliferation: Interplay with the estrogen receptor

In the present report, we investigated the action of retinoic acid (RA) on the transactivation of the epidermal growth factor receptor (EGFR) gene promoter. In a previous study, we showed that the estrogen receptor (ER) alpha activated by 17beta-estradiol (E2) increased EGFR expression by enhancing the binding of the transcription factor Sp1 to the EGFR minimal promoter in HeLa cells. Here, we demonstrate that ligand-activated RA receptor (RAR) alpha inhibited EGFR transactivation by competing with Sp1 for binding to the same promoter fragment in the same cell model. When RARalphaand ERalpha were coexpressed, the inhibitory effect of RA on transactivation of the EGFR promoter counteracted the enhancement induced by E2-activated ERalpha and became more pronounced in the presence of ligand-free ERalpha. In the MCF7 breast cancer cell line, which endogenously expresses RARalpha and ERalpha, RA exerted anti-proliferative effects in the presence of ligand-free ERalpha. Moreover, interplay between the pathways mediated by the two receptors was observed, as RA counteracted E2-induced cell proliferation. Our results suggest that the interference with the activity of Sp1 on the EGFR promoter could be related to the observed RA-mediated growth suppression of breast cancer cells.