Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features.
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.
Department of Pathology, Hacettepe University, Ankara, Turkey.
Gulnur
G
Guler
Cigdem
C
Himmetoglu
Rafael E
RE
Jimenez
Susan M
SM
Geyer
Wenle P
WP
Wang
Stefan
S
Costinean
Robert T
RT
Pilarski
Carl
C
Morrison
Dinc
D
Suren
Jianhua
J
Liu
Jingchun
J
Chen
Jyoti
J
Kamal
Charles L
CL
Shapiro
Kay
K
Huebner
D017766:Acid Anhydride Hydrolases / Q000032:analysis; D000328:Adult; D019313:BRCA1 Protein / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis*; D064447:Checkpoint Kinase 2; D016009:Chi-Square Distribution; D004249:DNA Damage; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006657:Histones / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis; D016017:Odds Ratio; D010088:Oxidoreductases / Q000032:analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D066247:Receptor, ErbB-4; D016019:Survival Analysis; D013997:Time Factors; D046888:Tissue Array Analysis; D050656:Transcription Factor AP-2 / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D066246:ErbB Receptors; D006657:Histones; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D017346:Protein Serine-Threonine Kinases; D066247:Receptor, ErbB-4; D050656:Transcription Factor AP-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000074584:WW Domain-Containing Oxidoreductase; D000099170:Bis(5'-adenosyl)triphosphatase; C492913:BRCA1 protein, human; C468783:H2AX protein, human; C495901:TP53 protein, human; C486071:WWOX protein, human; C587689:ERBB4 protein, human; C578634:CHEK2 protein, human