Fhit, Wwox and AP2 Expression Levels Correlate with Basal Phenotype in Breast Cancer
G Guler, K Huebner, C Himmetoglu Ussakli, R Jimenez, S Constinean, S Volinia, RT Pilarski, M Hayran, CL Shapiro. Hacettepe University, Ankara, Turkey; The Ohio State University, Columbus, OH; Institute of Oncology Hacettepe University, Ankara, Turkey
Background: Expression of Fhit and Wwox proteins, tumor suppressors encoded by fragile loci FRA3B and FRA16D, are concordantly lost in breast cancers. The current study examined correlations among Fhit, Wwox, transcription factors AP2 and AP2, cytokeratins 5/6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), Her2 and their associations with breast cancer phenotypes.
Design: 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, nuclear AP2 and AP2. Cytoplasmic Fhit and Wwox staining was scored according to staining intensity. ER, PR and Her2 status of tumors was from records. Correlations among immunohistochemical markers and tumor subtypes were assessed by univariate and multivariate statistical methods.
Results: Triple negative tumors showed more frequent expression of EGFR, CK5/6 (p<0.001) and AP2 (p = 0.003) and more frequent loss of Fhit and Wwox (p<0.001), with inverse correlation between Fhit, Wwox and EGFR ER, PR expression (p<0.001). Reduced Fhit expression was more common in Her2 and AP2 positive cases (p<0.001, p=0.002). There was direct correlation between Fhit and Wwox (p<0.001) and a borderline positive relation between AP2 and (p=0.054).
Conclusions: Results suggest that reduced Fhit, Wwox and nuclear AP2 expression have roles in pathogenesis of basal-like differentiation in breast cancer. Alteration of expression of fragile site genes occurs in most of these cancers and may contribute to defects in DNA repair, as observed in BRCA1-deficient cancers. Thus DNA damage response checkpoint proteins could be targets for treatment.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 29, Tuesday Afternoon