Ethanol-induced ligand-independent activation of ER alpha mediated by cyclic AMP/PKA signaling pathway: An in vitro study on MCF-7 breast cancer cells
Fiche publication
Date publication
décembre 2007
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ETIQUE Nicolas, Pr FLAMENT Stéphane, Dr GRILLIER-VUISSOZ Isabelle
Tous les auteurs :
Etique N, Flament S, Lecomte J, Grillier-Vuissoz I
Lien Pubmed
Résumé
Alcohol consumption is an increased risk factor for hormone-dependent breast cancer but the underlying molecular bases are unknown. Several studies suggest that ethanol could activate the estrogen signaling pathway. We have performed an in vitro study in order to investigate the molecular players involved in this phenomenon. Exposure of MCF-7 breast cancer cells to ethanol induced an increase in the mRNA level of two well known estrogen target genes: progesterone receptor (PR) and pS2. This result was confirmed by an increase in luciferase activity in pEREtkLuc-transfected MCF-7 cells exposed to ethanol. These effects, whose intensity was similar to those of E2, were observed also in steroid-free medium and were inhibited by the antiestrogen ICI 182,780. This suggested a ligand-independent activation of ER alpha that was confirmed by the absence of ER alpha proteolysis in ethanol-treated cells. Using PKA inhibitor (1189), the study of phospho-CREB by Western blot and transfection experiments with a CRE-reporter construct demonstrated that PKA was involved in ethanol-induced transcription of ER alpha target genes. Adenylyl cyclase inhibition impaired the activation of estrogen signaling pathway induced by ethanol. The results obtained in vitro, are discussed in regard to alcohol consumption and relevance to humans.
Référence
Int J Oncol. 2007 Dec;31(6):1509-18.