title: Wnt signaling in triple negative breast cancer is associated with metastasis.
abstract: BACKGROUND
  Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.
  
  
  METHODS
  We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.
  
  
  RESULTS
  The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.
  
  
  CONCLUSIONS
  These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
authors.forename: Nandini
authors.initials: N
authors.lastname: Dey
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Barwick
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Moreno
authors.forename: Maja
authors.initials: M
authors.lastname: Ordanic-Kodani
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.forename: Gabriella
authors.initials: G
authors.lastname: Oprea-Ilies
authors.forename: Weining
authors.initials: W
authors.lastname: Tang
authors.forename: Charles
authors.initials: C
authors.lastname: Catzavelos
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Kerstann
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Mark
authors.initials: M
authors.lastname: Abramovitz
authors.forename: Mark
authors.initials: M
authors.lastname: Bouzyk
authors.forename: Pradip
authors.initials: P
authors.lastname: De
authors.affiliation: Edith Sanford Breast Cancer, Sanford Research, 2301 E 60th Street N, Sioux Falls, SD 57104, USA. brian.leyland-jones@sanfordhealth.org.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Leyland-Jones
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002465:Cell Movement; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D016612:Paraffin Embedding; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin