title: Epigallocatechin-3-gallate (EGCG) downregulates EGF-induced MMP-9 in breast cancer cells: involvement of integrin receptor α5β1 in the process.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR/ErbB1) is a transmembrane protein with tyrosine kinase activity activated mainly by ligand, EGF. Matrix metalloproteinases (MMPs) are a family of proteinases that catalyses the destruction of ECM, among which MMP-9 has important role in tumor cell invasion. Secretion of MMP-9 is stimulated by a variety of factors, EGFR being significant. Epigallocatechin-3-gallate (EGCG) is a major polyphenol of green tea that inhibits cell proliferation and invasion. Here, we study the effect of EGFR alone and in collaboration with fibronectin on the status of MMP-9 in human breast cancer cell MDA-MB-231 and its molecular mechanism; study the role of EGCG on the induced MMP-9; and elucidate the signaling molecules involved in the process.
  
  
  METHODS
  We performed zymography, immunoblots, real-time RT-PCR, cell adhesion assay, siRNA studies, and electrophoretic mobility shift assay to demonstrate the findings.
  
  
  RESULTS
  EGF induces MMP-9 activity and expression; FAK, PI3 K, and ERK are mainly involved in the process. EGF also causes the transactivation of MMP-9 gene by increasing the DNA binding activity of the transcription factors. EGCG downregulates EGF-induced MMP-9 expression by inhibiting the involved regulatory kinases. EGF collaborates with fibronectin to create a synergistic response, and EGCG inhibits the synergistic response in MDA-MB-231.
  
  
  CONCLUSIONS
  The study demonstrates the requirement of cross talk between cell matrix adhesion molecules and growth factor receptors to improve biological responses and shows FAK/ERK as the pivotal point of this convergence in human breast carcinoma cell line MDA-MB-231. We also establish EGCG as the potential anti-tumor agent in human breast carcinoma.
authors.affiliation: Department of Receptor Biology & Tumor Metastasis, Chittaranjan National Cancer Institute, 37, S P Mukherjee Road, Kolkata, West Bengal 700 026, India.
authors.forename: Triparna
authors.initials: T
authors.lastname: Sen
authors.forename: Amitava
authors.initials: A
authors.lastname: Chatterjee
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000819:agonists / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005353:Fibronectins; D039081:Integrin alpha5beta1; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D002392:Catechin; C045651:epigallocatechin gallate; C512478:EGFR protein, human; D066246:ErbB Receptors; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020780:Matrix Metalloproteinase 9