title: A novel anti-CCN1 monoclonal antibody suppresses Rac-dependent cytoskeletal reorganization and migratory activities in breast cancer cells.
abstract: CCN1, a secreted matrix-associated molecule, is involved in multiple cellular processes. Accumulating evidence supports that CCN1 plays an important role in tumorigenesis and progression of breast cancer. In this study, we have developed a novel CCN1 function-blocking monoclonal antibody (mAb), designated YM1B. YM1B binds to human CCN1 with high specificity, recognizing the native CCN1 structure with undisturbed disulfide linkages. Our analyses have mapped the YM1B recognition region to domain IV of CCN1, likely in proximity to the DM site. In breast cancer cells, CCN1 can induce actin reorganization, formation of lamellipodia, and cell migration/invasion through the αV integrins/Rac1/ERK signaling axis; these CCN1-dependent activities can be effectively suppressed by YM1B. Our results also suggest that YM1B may exert its CCN1-blocking effect by perturbing the interaction of CCN1 with vitronectin and fibronectin, which are ligands of αV integrins and instrumental for integrin activation. This CCN1-specific mAb may open a new potential avenue for therapeutic intervention of breast cancer progression.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan. sjleu@ym.edu.tw
authors.forename: Shr-Jeng
authors.initials: SJ
authors.lastname: Jim Leu
authors.forename: Jung-Sung
authors.initials: JS
authors.lastname: Sung
authors.forename: Meng-Ling
authors.initials: ML
authors.lastname: Huang
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Chen
authors.forename: Tsai-Wei
authors.initials: TW
authors.lastname: Tsai
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology; D001666:Binding Sites, Antibody; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D055515:Cysteine-Rich Protein 61 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D061986:MCF-7 Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019096:Vitronectin / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D000939:Epitopes; D005353:Fibronectins; D039564:Integrin alphaV; C107953:RAC1 protein, human; D019096:Vitronectin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020830:rac1 GTP-Binding Protein