Wwox and Ap2γ expression levels predict tamoxifen response

Purpose: Assessment of expression levels of Wwox, Wwox- interacting proteins Ap2 alpha, Ap2 gamma, and ErbB4, the Ap2 gamma transcriptional target protein Her2, and the possible Ap2 alpha transcriptional target Prka Rl alpha, 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 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 PrkaRl alpha, Ap2 gamma, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis,Wwox, Prka Rla, Ap2 gamma, 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 gamma 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 gamma emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.