Wwox and Ap2γ expression levels predict tamoxifen response
Wwox and Ap2γ expression levels predict tamoxifen response
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DOI：
10.1158/1078-0432.ccr-07-1282
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发表时间：
2007-10-15
影响因子：
11.5
通讯作者：
Huebner, Kay
中科院分区：
文献类型：
--
作者：
Guler, Gulnur;Iliopoulos, Dimitrios;Huebner, Kay
目的：研究乳腺癌中WWOX、WWOX相互作用蛋白AP2α、AP2伽马和ErbB4、AP2伽马转录靶蛋白Her2和可能的AP2α转录靶标Prka RLα的表达水平，以确定它们在他莫昔芬耐药中的作用。实验设计：对51例对他莫昔芬敏感的乳腺癌和38例对他莫昔芬耐药、雌激素受体α阳性的乳腺癌组织切片进行上述蛋白和孕激素受体(PR)染色。结果：绝经状态、肿瘤、淋巴结、分期、PR缺失、WWOX表达缺失、PrkaR1α、AP2γ和Her2高表达与三苯氧胺抵抗显著相关。在多变量分析中，Wwox、Prka RLA、AP2γ和ErbB4是三苯氧胺耐药的独立标志物。在预测耐药方面，Wwox表达下调优于PR，尤其是在高危患者，而核AP2-Gamma表达优于Her2，尤其是在低风险患者。结论：这些结果揭示了本体内研究中评估的标记蛋白之间的复杂关系，为预测他莫昔芬治疗的疗效提供了新的标志物，并可能成为乳腺癌治疗的新靶点。WWOX和AP2伽马作为新的生物标志物出现，在预测他莫昔芬疗效方面可能优于PR和Her2。
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.