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Wwox and Ap2 Expression Levels Predict Tamoxifen Response

Authors' Affiliations: ¹ Department of Pathology and ² Institute of Oncology, Departments of Medical Oncology and ³ Preventive Oncology, Hacettepe University, Ankara, Turkey and ⁴ Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio

Requests for reprints: Gulnur Guler, Department of Pathology, Hacettepe University, Ankara, Turkey. Phone: 90-312-305-1563; Fax: 90-312-428-2324; E-mail: gguler{at}hacettepe.edu.tr.

Purpose: Assessment of expression levels of Wwox, Wwox-interacting proteins Ap2, Ap2, and ErbB4, the Ap2 transcriptional target protein Her2, and the possible Ap2 transcriptional target PrkaRI, 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.

Experimental Design: Tissue sections from 51 tamoxifen-sensitive and 38 tamoxifen-resistant, estrogen receptor –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 PrkaRI, Ap2, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis, Wwox, PrkaRI, Ap2, 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 Ap2 expression was better than Her2, especially in low-risk patients.

Conclusion: 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 Ap2 emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.