title: ERK/MAPK pathways play critical roles in EGFR ligands-induced MMP1 expression.
abstract: Activation of epidermal growth factor receptor (EGFR)-induced signaling pathways has been correlated with tumor progression, invasion and metastasis in a variety of cancers including breast carcinoma, but the underlying mechanism is not well understood. Matrix metalloproteinases (MMPs) have been implicated in cancer invasion and metastasis for their extracellular matrix (ECM)-proteolytic activity. However, the correlation of EGFR pathway with MMP expression in breast cancer has not been established. The aim of this study was to elucidate the interaction between EGFR ligands and their signaling pathway and MMP expression which might be closely related with breast cancer pathogenesis. We investigated the effect of EGF ligands on the MMP1 expression in SK-BR3 cell lines using RT-PCR, Western blot, ELISA and EMSA. Treatments with EGFR ligands, EGF and TGF-α enhanced MMP1 expression at the level of both transcription and translation in SK-BR3 breast cancer cells. EGF and TGF-α treatment resulted in phosphorylation of EGFR, and consequent activation of ERK1/2 pathway. Tyrosine kinase inhibitors of HER family, erlotinib, lapatinib and canertinib suppressed EGF-ligands mediated MMP1 overexpression. The specific MEK inhibitor, U0126, significantly blocks EGF and TGF-α-mediated ERK1/2 activation and subsequent MMP1 induction in SK-BR3 cells. Inhibition of the Akt pathway with LY294002 paradoxically augmented MMP1 expression by reciprocal activation of ERK1/2 pathway. These data suggest that invasive potential of SK-BR3 cell would be affected by these drugs by suppression of EGFR ligands-induced MMP1 expression.
authors: Division of Oncology, Department of Medicine, Seoul St. Mary's Hospital, Catholic University School of Medicine, 505 Banpo-Dong, Seocho-Gu, Seoul, Republic of Korea.
authors: Sarah
authors: S
authors: Park
authors: Hae Hyun
authors: HH
authors: Jung
authors: Yeon Hee
authors: YH
authors: Park
authors: Jin Seok
authors: JS
authors: Ahn
authors: Young-Hyuck
authors: YH
authors: Im
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D020890:Neuregulin-1; D009570:Nitriles; D016211:Transforming Growth Factor alpha; C113580:U 0126; C087230:heregulin beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1