title: FOXO3 expression during colorectal cancer progression: biomarker potential reflects a tumour suppressor role.
abstract: BACKGROUND
  In previous studies, the Forkhead/winged-helix-box-class-O3 (FOXO3) transcription factor has displayed both tumour suppressive and metastasis-promoting properties.To clarify its role in human colorectal cancer (CRC) progression, we examined in vivo FOXO3 expression at key points of the metastatic cascade.
  
  
  METHODS
  Formalin-fixed paraffin-embedded resection specimens from normal colon, adenomas, primary CRC specimens of different pathological stage and CRC specimens with matched liver metastases were used to generate three separate custom-designed tissue microarray (TMA) representations of metastatic progression. Triplicate cores, immunostained for FOXO3 were scored semiquantitatively by two investigators.
  
  
  RESULTS
  The FOXO3 expression is significantly reduced in CRC specimens compared with normal tissue, and progressive FOXO3 downregulation is associated with advancing pathological stage. In addition, recurrent stage I/II primary tumours show a significantly lower FOXO3 expression compared with stage-matched non-recurrent tumours. When stratified according to high and low FOXO3 expression, mean disease-free survival in the low-expressing group was 28 months (95% CI 15.8-50.6) compared with 64 months (95% CI 52.9-75.4) in the high-expressing group.
  
  
  CONCLUSIONS
  We have demonstrated an association between low FOXO3 expression and CRC progression in vivo using purpose-designed TMAs. Forkhead/winged-helix-box-class-O3 may represent a novel biomarker of nodal and distant disease spread with clinical utility in CRC.
authors.affiliation: Cancer Research UK Centre, University of Southampton, Somers Cancer Sciences Building, Southampton General Hospital, University Hospital Southampton, Tremona Road, Southampton, UK. m.bullock@soton.ac.uk
authors.forename: M D
authors.initials: MD
authors.lastname: Bullock
authors.forename: A
authors.initials: A
authors.lastname: Bruce
authors.forename: R
authors.initials: R
authors.lastname: Sreekumar
authors.forename: N
authors.initials: N
authors.lastname: Curtis
authors.forename: T
authors.initials: T
authors.lastname: Cheung
authors.forename: I
authors.initials: I
authors.lastname: Reading
authors.forename: J N
authors.initials: JN
authors.lastname: Primrose
authors.forename: C
authors.initials: C
authors.lastname: Ottensmeier
authors.forename: G K
authors.initials: GK
authors.lastname: Packham
authors.forename: G
authors.initials: G
authors.lastname: Thomas
authors.forename: A H
authors.initials: AH
authors.lastname: Mirnezami
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D025521:Tumor Suppressor Proteins