title: Action of retinoic acid receptor on EGFR gene transactivation and breast cancer cell proliferation: Interplay with the estrogen receptor.
abstract: 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) α activated by 17β-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) α inhibited EGFR transactivation by competing with Sp1 for binding to the same promoter fragment in the same cell model. When RARα and ERα were coexpressed, the inhibitory effect of RA on transactivation of the EGFR promoter counteracted the enhancement induced by E₂-activated ERα and became more pronounced in the presence of ligand-free ERα. In the MCF7 breast cancer cell line, which endogenously expresses RARα and ERα, RA exerted anti-proliferative effects in the presence of ligand-free ERα. 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.
authors.affiliation: CNR, National Research Council of Italy, Institute of Molecular Biology and Pathology, Rome, Italy. luisa.salvatori@ifo.it
authors.forename: Luisa
authors.initials: L
authors.lastname: Salvatori
authors.forename: Linda
authors.initials: L
authors.lastname: Ravenna
authors.forename: Francesca
authors.initials: F
authors.lastname: Caporuscio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Principessa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Coroniti
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Matteo Antonio
authors.initials: MA
authors.lastname: Russo
authors.forename: Elisa
authors.initials: E
authors.lastname: Petrangeli
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018773:Genes, erbB-1; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020239:Receptor Cross-Talk / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016329:Sp1 Transcription Factor; D004958:Estradiol; D014212:Tretinoin