title: CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness.
abstract: The immunoglobulin superfamily glycoprotein CD147 (emmprin; basigin) is associated with an invasive phenotype in various types of cancers, including malignant breast cancer. We showed recently that up-regulation of CD147 in non-transformed, non-invasive breast epithelial cells is sufficient to induce an invasive phenotype characterized by membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invadopodia activity (Grass, G. D., Bratoeva, M., and Toole, B. P. (2012) Regulation of invadopodia formation and activity by CD147. J. Cell Sci. 125, 777-788). Here we found that CD147 induces breast epithelial cell invasiveness by promoting epidermal growth factor receptor (EGFR)-Ras-ERK signaling in a manner dependent on hyaluronan-CD44 interaction. Furthermore, CD147 promotes assembly of signaling complexes containing CD147, CD44, and EGFR in lipid raftlike domains. We also found that oncogenic Ras regulates CD147 expression, hyaluronan synthesis, and formation of CD147-CD44-EGFR complexes, thus forming a positive feedback loop that may amplify invasiveness. Last, we showed that malignant breast cancer cells are heterogeneous in their expression of surface-associated CD147 and that high levels of membrane CD147 correlate with cell surface EGFR and CD44 levels, activated EGFR and ERK1, and activated invadopodia. Future studies should evaluate CD147 as a potential therapeutic target and disease stratification marker in breast cancer.
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology and.
authors.forename: G Daniel
authors.initials: GD
authors.lastname: Grass
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology and.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Tolliver
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology and.
authors.forename: Momka
authors.initials: M
authors.lastname: Bratoeva
authors.affiliation: From the Department of Regenerative Medicine and Cell Biology and; the Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425. Electronic address: toolebp@musc.edu.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Toole
mesh_terms: D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C497886:BSG protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D051926:Basigin; C512478:EGFR protein, human; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3
keywords: Breast Cancer; CD147; CD44; Epidermal Growth Factor Receptor (EGFR); Hyaluronate; Invadopodia; Ras