Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features

Breast Cancer Res Treat. 2011 Sep;129(2):421-32. doi: 10.1007/s10549-010-1248-6. Epub 2010 Nov 11.

Abstract

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Anhydride Hydrolases / analysis
  • Adult
  • BRCA1 Protein / analysis
  • Breast Neoplasms / chemistry*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins / analysis*
  • Checkpoint Kinase 2
  • Chi-Square Distribution
  • DNA Damage*
  • Disease-Free Survival
  • ErbB Receptors / analysis
  • Female
  • Histones / analysis
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Logistic Models
  • Middle Aged
  • Neoplasm Proteins / analysis
  • Odds Ratio
  • Oxidoreductases / analysis
  • Prognosis
  • Proportional Hazards Models
  • Protein-Serine-Threonine Kinases / analysis
  • Receptor, ErbB-4
  • Survival Analysis
  • Time Factors
  • Tissue Array Analysis
  • Transcription Factor AP-2 / analysis
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Proteins / analysis
  • WW Domain-Containing Oxidoreductase

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Cell Cycle Proteins
  • H2AX protein, human
  • Histones
  • Neoplasm Proteins
  • TP53 protein, human
  • Transcription Factor AP-2
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • fragile histidine triad protein
  • Oxidoreductases
  • WW Domain-Containing Oxidoreductase
  • WWOX protein, human
  • Checkpoint Kinase 2
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-4
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Acid Anhydride Hydrolases