Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis
Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis
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DOI：
10.1038/nature04225
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发表时间：
2005-12-15
期刊：
影响因子：
64.8
通讯作者：
Shang, YF
中科院分区：
文献类型：
--
作者：
Wu, HJ;Chen, YP;Shang, YF
他莫昔芬是一种选择性雌激素受体调节剂，已被用于治疗所有阶段的对雌激素敏感的乳腺癌。然而，他莫昔芬在子宫中显示出部分雌激素活性，并且其使用与子宫内膜癌的发病率增加有关。这些观察结果的分子解释尚不清楚。在这里，我们表明，他莫昔芬和雌激素有不同的，但重叠的靶基因谱。在重叠的靶基因中，我们确定了一个配对盒基因PAX2，它在子宫内膜的细胞增殖和癌变中起着至关重要的作用。我们的实验表明，PAX2在子宫内膜癌中被雌激素和他莫昔芬激活，但在正常子宫内膜中不被激活，并且这种激活与PAX2启动子的癌症相关低甲基化有关。
Tamoxifen, a selective oestrogen receptor modulator, has been used in the treatment of all stages of hormone-responsive breast cancer. However, tamoxifen shows partial oestrogenic activity in the uterus and its use has been associated with an increased incidence of endometrial cancer. The molecular explanation for these observations is not known. Here we show that tamoxifen and oestrogen have distinct but overlapping target gene profiles. Among the overlapping target genes, we identify a paired-box gene, PAX2, that is crucially involved in cell proliferation and carcinogenesis in the endometrium. Our experiments show that PAX2 is activated by oestrogen and tamoxifen in endometrial carcinomas but not in normal endometrium, and that this activation is associated with cancer-linked hypomethylation of the PAX2 promoter.