title: Extra-virgin olive oil polyphenols inhibit HER2 (erbB-2)-induced malignant transformation in human breast epithelial cells: relationship between the chemical structures of extra-virgin olive oil secoiridoids and lignans and their inhibitory activities on the tyrosine kinase activity of HER2.
abstract: 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.
authors.affiliation: Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IdIBGi), Spain. jmenendez@ico.scs.es
authors.forename: Javier A
authors.initials: JA
authors.lastname: Menendez
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.forename: Cristina
authors.initials: C
authors.lastname: Oliveras-Ferraros
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Villalba
authors.forename: Alegria
authors.initials: A
authors.lastname: Carrasco-Pancorbo
authors.forename: Alberto
authors.initials: A
authors.lastname: Fernandez-Gutierrez
authors.forename: Antonio
authors.initials: A
authors.lastname: Segura-Carretero
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D039823:Iridoids / Q000737:chemistry*; D017705:Lignans / Q000737:chemistry*; D000069463:Olive Oil; D010636:Phenols / Q000494:pharmacology*; D010938:Plant Oils / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics
chemical_list: D005419:Flavonoids; D039823:Iridoids; D017705:Lignans; D000069463:Olive Oil; D010636:Phenols; D010938:Plant Oils; D059808:Polyphenols; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases