title: Monoclonal antibody against the ectodomain of E-cadherin (DECMA-1) suppresses breast carcinogenesis: involvement of the HER/PI3K/Akt/mTOR and IAP pathways.
abstract: OBJECTIVE
  Although targeted therapies against HER2 have been one of the most successful therapeutic strategies for breast cancer, patients eventually developed acquired resistance from compensatory upregulation of alternate HERs and mitogen-activated protein kinase-phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling. As we and others have shown that the soluble ectodomain fragment of E-cadherin exerts prooncogenic effects via HER1/2-mediated binding and activation of downstream prosurvival pathways, we explored whether targeting this ectodomain [DECMA-1 monoclonal antibody (mAb)] was effective in the treatment of HER2-positive (HER2(+)) breast cancers.
  
  
  METHODS
  MMTV-PyMT transgenic mice and HER2(+)/E-cadherin-positive MCF-7 and BT474 trastuzumab-resistant (TtzmR) cells were treated with the DECMA-1 mAb. Antitumor responses were assessed by bromodeoxyuridine incorporation, apoptosis, and necrosis. The underlying intracellular prooncogenic pathways were explored using subcellular fractionation, immunoprecipitation, fluorescence microscopy, and immunoblotting.
  
  
  RESULTS
  Treatment with DECMA-1 mAb significantly delayed tumor onset and attenuated tumor burden in MMTV-PyMT mice by reducing tumor cell proliferation and inducing apoptosis without any detectable cytotoxicity to mice or end-organs. In vitro treatment of MCF-7 and BT474 TtzmR cells reduced proliferation and induced cancer cell apoptosis. Importantly, this inhibition of breast tumorigenesis was due to concomitant downregulation, via ubiquitin-mediated degradation through the lysosome and proteasome pathways, of all HER family members, components of downstream PI3K/Akt/mTOR prosurvival signaling and suppression of inhibitor of apoptosis proteins.
  
  
  CONCLUSIONS
  Our results establish that the E-cadherin ectodomain-specific mAb DECMA-1 inhibits Ecad(+)/HER2(+) breast cancers by hindering tumor growth and inducing apoptosis via downregulation of key oncogenic pathways involved in trastuzumab resistance, thereby establishing a novel therapeutic platform for the treatment of HER2(+) breast cancers.
authors.affiliation: Department of Emergency Medicine, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. sabine.brouxhon@stonybrook.edu
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Brouxhon
authors.forename: Stephanos
authors.initials: S
authors.lastname: Kyrkanides
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Teng
authors.forename: Veena
authors.initials: V
authors.lastname: Raja
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Stephen
authors.initials: S
authors.lastname: Byers
authors.forename: Andrew
authors.initials: A
authors.lastname: Silberfeld
authors.forename: Carmen
authors.initials: C
authors.lastname: Tornos
authors.forename: Li
authors.initials: L
authors.lastname: Ma
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000276:immunology*; D063646:Carcinogenesis / Q000187:drug effects* / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D061986:MCF-7 Cells; D051058:Oncogene Protein v-akt / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D015820:Cadherins; D051034:Inhibitor of Apoptosis Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human