Wwox and Ap2gamma expression levels predict tamoxifen response.
OBJECTIVE
Assessment of expression levels of Wwox, Wwox-interacting proteins Ap2alpha, Ap2gamma, and ErbB4, the Ap2gamma transcriptional target protein Her2, and the possible Ap2alpha transcriptional target PrkaRIalpha, in breast cancers, to determine their roles in tamoxifen resistance. The hypothesis was that sequestration of Wwox interactors in the cytoplasm might control tamoxifen response.


METHODS
Tissue sections from 51 tamoxifen-sensitive and 38 tamoxifen-resistant, estrogen receptor alpha-positive breast cancers were stained for the above proteins, as well as progesterone receptor (PR). The relation of tamoxifen resistance and other clinical features, with level of expression of these proteins, and pairwise correlations among various immunohistochemical markers were determined.


RESULTS
Menopausal status, tumor, node, and stage, loss of PR, lost or reduced expression of Wwox, and high level of expression of PrkaRIalpha, Ap2gamma, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis, Wwox, PrkaRIalpha, Ap2gamma, and ErbB4 were found to be independent markers of tamoxifen resistance. Reduced Wwox expression was better than PR in prediction of resistance, especially in high-risk patients, and nuclear Ap2gamma expression was better than Her2, especially in low-risk patients.


CONCLUSIONS
The results illustrate the complex relationships among the marker proteins assessed in this in vivo study and suggest new markers for prediction of response to tamoxifen treatment as well as possible new targets for treatment of breast cancer. Wwox and Ap2gamma emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.
Guler
Gulnur
G
Department of Pathology, Hacettepe University, Ankara, Turkey. gguler@hacettepe.edu.tr
Iliopoulos
Dimitrios
D
Guler
Nilufer
N
Himmetoglu
Cigdem
C
Hayran
Mutlu
M
Huebner
Kay
K
D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008593:Menopause; D008875:Middle Aged; D010088:Oxidoreductases / Q000096:biosynthesis*; D066247:Receptor, ErbB-4; D012306:Risk; D013629:Tamoxifen / Q000494:pharmacology*; D050656:Transcription Factor AP-2 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D000074584:WW Domain-Containing Oxidoreductase
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4