Crosstalk between adenosine receptor (A2A isoform) and ERα mediates ethanol action in MCF-7 breast cancer cells

Abstract

Alcohol consumption increases the risk of breast cancer but the underlying mechanisms are not well understood. We have shown previously that ethanol activates ER signalling pathway in a cAMP/PKA-mediated ligand-independent manner. Since the activation of A2A adenosine receptor (A2AAR) by ethanol has been reported in other cell types, here we tested if cross-talk between this Gs-coupled receptor and ERα could be involved in ethanol effects in breast cancer cells. Our study shows that A2AAR is expressed and functional in the hormone-dependent breast cancer cell line MCF-7. Interestingly, activation of this receptor by the selective agonist CGS21680 stimulates the transcription of progesterone receptor, a well known estrogen target gene. CGS21680 also stimulates the pEREtkLuc reporter activity in transfected MCF-7 cells, an effect antagonized by the antiestrogen ICI182,780. Moreover, CGS21680 stimulates the proliferation of MCF-7 cells similarly to E2. Finally, the A2AAR antagonist MSX-3 inhibits the ethanol-induced activation of ERα signalling pathway. These results demonstrate cross-talk between A2AAR and ERα that is involved in ethanol action. This could open new perspectives for the therapy of estrogen-dependent breast cancer.