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

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 ERalpha 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 ERalpha signalling pathway. These results demonstrate cross-talk between A2AAR and ERalpha that is involved in ethanol action. This could open new perspectives for the therapy of estrogen-dependent breast cancer.