Oleuropein and hydroxytyrosol activate GPER/ GPR30‐dependent pathways leading to apoptosis of ER‐negative SKBR3 breast cancer cells

SCOPE: We have previously demonstrated that oleuropein (OL) and hydroxytyrosol (HT) reduce 17β‐estradiol‐mediated proliferation in MCF‐7 breast cancer (BC) cells without affecting the classical genomic action of estrogen receptor (ER), but activating instead the ERK1/2 pathway. Here, we hypothesized that this inhibition could be mediated by a G‐protein‐coupled receptor named GPER/GPR30. Using the ER‐negative and GPER‐positive SKBR3 BC cells as experimental model, we investigated the effects of OL and HT on GPER‐mediated activation of downstream pathways. METHODS AND RESULTS: Docking simulations and ligand‐binding studies evidenced that OL and HT are able to bind GPER. MTT cell proliferation assays revealed that both phenols reduced SKBR3 cell growth; this effect was abolished silencing GPER. Focusing on OL and HT GPER‐mediated pathways, using Western blot analysis we showed a sustained ERK1/2 activation triggering an intrinsic apoptotic pathway. CONCLUSION: Showing that OL and HT work as GPER inverse agonists in ER‐negative and GPER‐positive SKBR3 BC cells, we provide novel insights into the potential of these two molecules as tools in the therapy of this subtype of BC.