title: Expression of the novel Wnt receptor ROR2 is increased in breast cancer and may regulate both β-catenin dependent and independent Wnt signalling.
abstract: OBJECTIVE
  Wnt signalling has been implicated in breast cancer, and in particular aberrant β-catenin-independent Wnt signalling has been associated with breast cancer metastasis and Tamoxifen resistance. Despite Wnt pathway involvement in many human cancers, attempts to target the pathway therapeutically have been disappointing. The recent discovery that the receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a novel Wnt receptor provides a potential new therapeutic and diagnostic target.
  
  
  METHODS
  To clarify the role of ROR2 in breast cancer, we investigated its expression via ROR2 immunohistochemistry in a clinical cohort of breast cancer patients, and via in vitro studies incorporating both overexpression and knock-down of ROR2.
  
  
  RESULTS
  ROR2 was expressed in the majority of breast cancer patients (87%), including those classed as triple negative. Breast cancer patients expressing ROR2 had a significantly shorter overall survival than those lacking ROR2 expression (P < 0.05). Overexpression of ROR2 in the mammary epithelial cell line, MCF10A, increased both β-catenin-dependent and β-catenin-independent targets and decreased cell adhesion. Knock-down of ROR2 in the breast cancer cell lines, MDA-MB-453 and HCC1143, decreased both β-catenin-dependent and β-catenin-independent targets and increased cell adhesion. Treatment of ROR2-expressing breast cancer cells with the novel berberine derivative, NAX53, significantly inhibited cell proliferation and migration.
  
  
  CONCLUSIONS
  This is the first study to report the expression of ROR2 in breast cancer. Breast cancer patients expressing ROR2 had a significantly worse prognosis than those lacking ROR2. ROR2 may regulate both β-catenin-dependent and β-catenin-independent Wnt signalling pathways, and represents a potential diagnostic and therapeutic target.
authors.affiliation: Adult Cancer Program, Level 2, Metastasis Research Group, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, UNSW, NSW, 2052, Australia, c.henry@student.unsw.edu.au.
authors.forename: C
authors.initials: C
authors.lastname: Henry
authors.forename: A
authors.initials: A
authors.lastname: Quadir
authors.forename: N J
authors.initials: NJ
authors.lastname: Hawkins
authors.forename: E
authors.initials: E
authors.lastname: Jary
authors.forename: E
authors.initials: E
authors.lastname: Llamosas
authors.forename: D
authors.initials: D
authors.lastname: Kumar
authors.forename: B
authors.initials: B
authors.lastname: Daniels
authors.forename: R L
authors.initials: RL
authors.lastname: Ward
authors.forename: C E
authors.initials: CE
authors.lastname: Ford
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000166:cytology / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors