title: Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2gamma expression levels correlate with basal phenotype in breast cancer.
abstract: BACKGROUND
  The expression of fragile histidine triad protein (Fhit) and WW domain-containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2alpha and AP2gamma, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) and their associations with breast cancer phenotypes.
  
  
  METHODS
  Tissue microarrays constructed from 837 breast cancer blocks were immunostained. Expression in >10% of tumor cells was considered positive for cytoplasmic CK5/6, membranous EGFR, and nuclear AP2alpha and AP2gamma. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR, and HER-2 status of tumors was derived from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods.
  
  
  RESULTS
  Triple-negative tumors had more frequent expression of EGFR, CK5/6 (P < .001), and AP2gamma (P = .003) and more frequent loss of Fhit and Wwox (P < .001), and an inverse correlation was observed between Fhit, Wwox expression and EGFR, ER, and PR expression (P < .001). Reduced Fhit expression was more common in HER-2-positive and AP2gamma-positive cases (P < .001 and P = .002, respectively). There was a direct correlation noted between Fhit and Wwox (P < .001) and a borderline positive relation between AP2alpha and AP2gamma (P = .054).
  
  
  CONCLUSIONS
  The results from this investigation suggested that reduced expression levels of Fhit, Wwox, and nuclear AP2gamma have roles in the pathogenesis of basal-like differentiation in breast cancer. Alteration in the expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in breast cancer 1 (BRCA1)-deficient cancers. Thus, DNA damage response checkpoint proteins may be targets for treatment.
authors.affiliation: Department of Pathology, Hacettepe University, Ankara, Turkey.
authors.forename: Gulnur
authors.initials: G
authors.lastname: Guler
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.forename: Cigdem
authors.initials: C
authors.lastname: Himmetoglu
authors.forename: Rafael E
authors.initials: RE
authors.lastname: Jimenez
authors.forename: Stefan
authors.initials: S
authors.lastname: Costinean
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Robert T
authors.initials: RT
authors.lastname: Pilarski
authors.forename: Mutlu
authors.initials: M
authors.lastname: Hayran
authors.forename: Charles L
authors.initials: CL
authors.lastname: Shapiro
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000556:secondary; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000556:secondary; D002454:Cell Differentiation; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D053555:Keratin-5 / Q000378:metabolism; D053553:Keratin-6 / Q000378:metabolism; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D010641:Phenotype; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D046888:Tissue Array Analysis; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase; D055815:Young Adult; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D053555:Keratin-5; D053553:Keratin-6; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C486071:WWOX protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human