Depending on their structure, some
polyphenols (e.g.
flavonoids) abundantly found in plant-derived beverages such as
green tea can efficiently inhibit
tyrosine kinase and
serine/threonine kinase activities. Extra-virgin
olive oil (EVOO - the juice of the olive obtained solely by pressing and consumed without any further refining process) is unique among other
vegetable oils because of the high level of naturally occurring phenolic compounds. We explored the ability of EVOO
polyphenols to modulate HER2
tyrosine kinase receptor-induced in vitro transformed phenotype in human breast epithelial cells. Using MCF10A normal breast epithelial cells retrovirally engineered to overexpress the wild-type sequence of human HER2, we further determined the relationship between chemical structures of EVOO-derived phenolics and their inhibitory activities on the
tyrosine kinase activity of the HER2
oncoprotein. When the activation (phosphorylation) status of HER2 was semi-quantitatively measured the
secoiridoids blocked HER2 signaling by rapidly reducing the activation status of the 1248
tyrosine residue (Y1248), the main autophosphorylation site of HER2. EVOO-derived single
phenols tyrosol and
hydroxytyrosol and the
phenolic acid elenolic acid failed to significantly decrease HER2
tyrosine kinase activity. The anti-HER2
tyrosine kinase activity IC50 values were up to 5-times lower in the presence of EVOO-derived
lignans and
secoiridoids than in the presence of EVOO-derived single
phenols and phenolic
acids. EVOO
polyphenols induced strong tumoricidal effects by selectively triggering high levels of apoptotic cell death in HER2-positive MCF10A/HER2 cells but not in MCF10A/pBABE matched control cells. EVOO
lignans and
secoiridoids prevented HER2-induced in vitro transformed phenotype as they inhibited colony formation of MCF10A/HER2 cells in soft-
agar. Our current findings not only molecularly support recent epidemiological evidence revealing that EVOO-related anti-
breast cancer effects primarily affect the occurrence of
breast tumors over-expressing the type I
receptor tyrosine kinase HER2 but further suggest that the stereochemistry of EVOO-derived
lignans and
secoiridoids might provide an excellent and safe platform for the design of new HER2 targeted anti-
breast cancer drugs.