title: Docosahexaenoic Acid Downregulates EGF-Induced Urokinase Plasminogen Activator and Matrix Metalloproteinase 9 Expression by Inactivating EGFR/ErbB2 Signaling in SK-BR3 Breast Cancer Cells.
abstract: Urokinase plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9) play crucial roles in tumor metastasis. Despite the well-known anticancer role of docosa-hexaenoic acid (DHA), its specific effect on ErbB2-mediated breast cancer metastasis is not fully clarified. In this study, we investigated the effect of DHA on epidermal growth factor (EGF)-induced uPA and MMP-9 activity, expression and cell invasion in SK-BR3 breast cancer cells and the possible mechanisms involved. The results showed that EGF (40 ng/ml) induced uPA and MMP-9 mRNA and protein expression, enzyme activity, and 100 μM DHA significantly inhibited EGF-induced uPA and MMP-9 mRNA, protein expression, enzyme activity, cell migration, and cell invasion. EGF increased protein expression and phosphorylation of EGF receptor (EGFR) and ErbB2 as well as of JNK2, ERK1/2, and Akt, and these changes were attenuated by DHA pretreatment. AG1478, an inhibitor of EGFR, also attenuated EGF-induced activation of EGFR, JNK2, ERK1/2, and Akt. Knocked down ErbB2 expression resulted in a similar inhibition of uPA and MMP-9 expression as noted by DHA and AG1478. Taken together, these results suggest that suppression of EGF-induced metastasis by DHA is likely through an inhibition of EGFR and ErbB2 protein expression and the downstream target uPA and MMP-9 activation in SK-BR3 human breast cancer cells.
authors.affiliation: a School of Nutrition, Chung Shan Medical University , Taichung , Taiwan.
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
authors.forename: Hsien-Tsung
authors.initials: HT
authors.lastname: Yao
authors.forename: Fang-Ju
authors.initials: FJ
authors.lastname: Cheng
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Lu
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Jer-Wei
authors.initials: JW
authors.lastname: Chang
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D012313:RNA / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D004281:Docosahexaenoic Acids; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; D012313:RNA; D018719:Erb-b2 Receptor Tyrosine Kinases; D014568:Urokinase-Type Plasminogen Activator; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C579270:MMP9 protein, human