title: (-)-Epigallocatechin-3-gallate down-regulates EGFR, MMP-2, MMP-9 and EMMPRIN and inhibits the invasion of MCF-7 tamoxifen-resistant cells.
abstract: The activation of the EGFR (epidermal growth factor receptor) signalling pathway is one of the key mechanisms underlying the development of resistance to tamoxifen in breast cancer patients. As EGCG [(-)-epigallocatechin-3-gallate], the most active catechin present in green tea, has been shown to down-regulate EGFR, we studied the effects of 10-100 μg/ml EGCG treatment on growth and invasion in a breast carcinoma cell line resistant to tamoxifen [MCF-7Tam (MCF-7 breast carcinoma cell line resistant to tamoxifen) cells] and parental MCF-7. A dose-dependent down-regulation of EGFR mRNA expression and protein level occurred after 50 μg/ml EGCG treatment of MCF-7Tam cells. EGFR molecules on the plasma membrane surface of MCF-7Tam cells significantly decreased. EGFR phosphorylation (Tyr-992, Tyr-1045 and Tyr-1068) was higher in MCF-7Tam than in MCF-7 and it was reduced by EGCG treatment. ERK (extracellular regulated kinase) and phospho-ERK p42/44 were also down-regulated by EGCG treatment and in vitro cell growth and invasion decreased. MMP-2 (matrix metalloproteinase-2) and MMP-9, which are implicated in cell invasion and metastasis, and EMMPRIN (extracellular matrix metalloproteinase inducer), a glycoprotein able to activate MMPs, were significantly reduced after 50 μg/ml EGCG treatment. In keeping with this, TIMP-1 (tissue inhibitor of metalloproteinases-1) and TIMP-2, which down-regulate MMPs, increased after EGCG treatment. Altogether, the present data demonstrated that EGCG could attenuate the tamoxifen-resistant phenotype of MCF-7Tam cells. EGCG could stop MCF-7Tam cell growth and in vitro invasion through down-regulation of EGFR and other molecules implicated in aggressive biological behaviour. The present data support the hypothesis that EGCG is an interesting molecule to be investigated in tamoxifen-resistant breast carcinoma.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. fulvia.farabegoli@unibo.it
authors.forename: Fulvia
authors.initials: F
authors.lastname: Farabegoli
authors.forename: Alessio
authors.initials: A
authors.lastname: Papi
authors.forename: Marina
authors.initials: M
authors.lastname: Orlandi
mesh_terms: D051926:Basigin / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000187:drug effects / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D013629:Tamoxifen; D019716:Tissue Inhibitor of Metalloproteinase-2; D051926:Basigin; D002392:Catechin; C045651:epigallocatechin gallate; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9