title: Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies.
abstract: BACKGROUND
  Annexin A2 (AnxA2), a calcium-dependent phospholipid binding protein, is abundantly present at the surface of triple-negative and Herceptin-resistant breast cancer cells. Interactions between cell-surface AnxA2 and tyrosine kinase receptors have an important role in the tumour microenvironment and act together to enhance tumour growth. The mechanism supporting this role is still unknown.
  
  
  METHODS
  The membrane function of AnxA2 was blocked by incubating cells with anti-AnxA2 antibodies. Western blotting, immunoprecipitation, immunofluorescence, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), flow cytometry, Clonogenic, and wound-healing assays were performed in this study.
  
  
  RESULTS
  We demonstrate that AnxA2 interacts with epidermal growth factor receptor (EGFR) at the cell surface and has an important role in cancer cell proliferation and migration by modulating EGFR functions. Blocking AnxA2 function at the cell surface by anti-AnxA2 antibody suppressed the EGF-induced EGFR tyrosine phosphorylation and internalisation by blocking its homodimerisation. Furthermore, addition of AnxA2 antibody significantly inhibited the EGFR-dependent PI3K-AKT and Raf-MEK-ERK downstream pathways under both EGF-induced and basal growth conditions, resulting in lower cell proliferation and migration.
  
  
  CONCLUSIONS
  These findings suggest that cell-surface AnxA2 has an important regulatory role in EGFR-mediated oncogenic processes by keeping EGFR signalling events in an activated state. Therefore, AnxA2 could potentially be used as a therapeutic target in triple-negative and Herceptin-resistant breast cancers.
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chaudhary
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Thamake
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: P
authors.initials: P
authors.lastname: Shetty
authors.affiliation: Department of Molecular and Medical Genetics, Texas Center for Health Disparities and the Institute for Cancer Research, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Vishwanatha
mesh_terms: D017306:Annexin A2 / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D015398:Signal Transduction; D000068878:Trastuzumab; D064726:Triple Negative Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*
chemical_list: D017306:Annexin A2; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068878:Trastuzumab