TY - JOUR
T1 - Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features
AU - Guler, Gulnur
AU - Himmetoglu, Cigdem
AU - Jimenez, Rafael E.
AU - Geyer, Susan M.
AU - Wang, Wenle P.
AU - Costinean, Stefan
AU - Pilarski, Robert T.
AU - Morrison, Carl
AU - Suren, Dinc
AU - Liu, Jianhua
AU - Chen, Jingchun
AU - Kamal, Jyoti
AU - Shapiro, Charles L.
AU - Huebner, Kay
N1 - Funding Information:
Acknowledgments Preliminary results of this study were presented at the 2010 USCAP Annual Meeting. We gratefully acknowledge the outstanding technical services of Susie Jones, Jason Bacher and David A. Kellough in the Pathology Core Facility of the Ohio State University, and Arda Günay, Ozlem Kalayci and Aybuke Kabaoglu of the Hacettepe University Department of Pathology, as well as the services of the Tissue Archive Shared Facility of the Ohio State University Comprehensive Cancer Center. We are especially grateful for the expert help of Sinan Ussakli in preparing files for statistical analysis and to Teresa Druck for help in editing and submitting the MS. Supported by US Public Health Service/National Cancer Institute Grants CA120516, CA132453, CA115965, pilot funding from the Molecular Biology and Cancer Genetics Program of the Ohio State University Comprehensive Cancer Center, Hacettepe University Research Fund Grant 05D11101003, and the Stephanie Spielman Foundation.
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - DNA damage response proteins
KW - Fhit
KW - Lymph node metastases
KW - Tissue microarrays
KW - Triple negative breast cancer
KW - Wwox
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U2 - 10.1007/s10549-010-1248-6
DO - 10.1007/s10549-010-1248-6
M3 - Article
C2 - 21069451
AN - SCOPUS:80052608676
SN - 0167-6806
VL - 129
SP - 421
EP - 432
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 2
ER -