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

Mol Nutr Food Res. 2014 Mar;58(3):478-89. doi: 10.1002/mnfr.201300323. Epub 2013 Sep 9.


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.

Keywords: Apoptosis; Breast cancer; GPER; Hydroxytyrosol; Oleuropein; SKBR3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Humans
  • Iridoids / pharmacology*
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured


  • GPER1 protein, human
  • Iridoids
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • 3,4-dihydroxyphenylethanol
  • oleuropein
  • Extracellular Signal-Regulated MAP Kinases
  • Phenylethyl Alcohol