DNA Damage-Associated Proteins in Triple Negative Breast Cancers
G Guler, C Himmetoglu, RE Jimenez, WP Wang, S Costinean, D Suren, M Hayran, C Shapiro, K Huebner. Hacettepe University, Ankara, Turkey; Ataturk Research and Education Hospital, Ankara, Turkey; Mayo Clinic, Rochester, MN; VA Medical Center at Baltimore, Baltimore, MD; The Ohio States University Medical Center, Columbus, OH
Background: Triple negative (TG) and basal-like (BL) tumors show frequent concordant loss of Fhit and Wwox proteins encoded by chromosomal fragile loci, FRA3B and FRA16D, that are exquisitely sensitive to genotoxic stress. In this study, the activation status of other DNA damage response-associated proteins was also examined in TN/BL tumors.
Design: TMAs were constructed from 479 breast cancer blocks and immunostaining performed. In addition to Fhit and Wwox, expression of basal markers CK5/6 and EGFR, DNA damage response proteins BRCA-1, p53, pChk2 and γH2AX, Wwox-interacting proteins Ap2α, Ap2γ, and ErbB3/B4 were scored. Expression was considered positive for tumors with: >10% cytoplasmic CK5/6, membranous EGFR, nuclear Ap2α/γ; >50% of cells with nuclear γH2AX, >25% with nuclear pChk2; any membrane staining of ErbB3 or ErbB4. Cytoplasmic Fhit and Wwox staining was scored for intensity: no staining, highly reduced, reduced or strong expression. BRCA-1 nuclear expression was scored as: high (>90%), reduced or negative.
Results: TN and BL (CK5/6 or EGFR+) tumors showed reduced Fhit, Wwox, BRCA-1 and ErbB3 (TN tumors, p<0.001,p=0.001,p=0.017,p=0.012 respectively; BL tumors, p=0.010,p=0.016, p=0.008,p=0.017 respectively) and more γH2AX, pChk2, p53, Ap2γ and ErbB4 expression (TN tumors, p=0.034,p=0.056, p<0.001, p<0.001, p=0.015 respectively; BL tumors, p=0.0182 p=0.030, p<0.001,p=0.001,p=0.028 respectively).
Conclusions: Absence of BRCA-1, with evidence of persistent activation of DNA damage response checkpoints in a large fraction of TN and BL tumors suggests that alteration or abrogation of signal pathways associated with cell cycle checkpoint control is characteristic of these tumors. Definition of specific DNA repair and checkpoint defects may provide new treatment targets.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 57, Tuesday Morning