title: Impact of mutant β-catenin on ABCB1 expression and therapy response in colon cancer cells.
abstract: BACKGROUND
  Colorectal cancers are often chemoresistant toward antitumour drugs that are substrates for ABCB1-mediated multidrug resistance (MDR). Activation of the Wnt/β-catenin pathway is frequently observed in colorectal cancers. This study investigates the impact of activated, gain-of-function β-catenin on the chemoresistant phenotype.
  
  
  METHODS
  The effect of mutant (mut) β-catenin on ABCB1 expression and promoter activity was examined using HCT116 human colon cancer cells and isogenic sublines harbouring gain-of-function or wild-type β-catenin, and patients' tumours. Chemosensitivity towards 24 anticancer drugs was determined by high throughput screening.
  
  
  RESULTS
  Cell lines with mut β-catenin showed high ABCB1 promoter activity and expression. Transfection and siRNA studies demonstrated a dominant role for the mutant allele in activating ABCB1 expression. Patients' primary colon cancer tumours shown to express the same mut β-catenin allele also expressed high ABCB1 levels. However, cell line chemosensitivities towards 24 MDR-related and non-related antitumour drugs did not differ despite different β-catenin genotypes.
  
  
  CONCLUSIONS
  Although ABCB1 is dominantly regulated by mut β-catenin, this did not lead to drug resistance in the isogenic cell line model studied. In patient samples, the same β-catenin mutation was detected. The functional significance of the mutation for predicting patients' therapy response or for individualisation of chemotherapy regimens remains to be established.
authors.affiliation: Charité Medical Faculty, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. ustein@mdc-berlin.de
authors.forename: U
authors.initials: U
authors.lastname: Stein
authors.forename: C
authors.initials: C
authors.lastname: Fleuter
authors.forename: F
authors.initials: F
authors.lastname: Siegel
authors.forename: J
authors.initials: J
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Kopacek
authors.forename: D A
authors.initials: DA
authors.lastname: Scudiero
authors.forename: K M
authors.initials: KM
authors.lastname: Hite
authors.forename: P M
authors.initials: PM
authors.lastname: Schlag
authors.forename: R H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: W
authors.initials: W
authors.lastname: Walther
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D050505:Mutant Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051176:beta Catenin / Q000235:genetics*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D050505:Mutant Proteins; D012333:RNA, Messenger; D051176:beta Catenin