Wu Huijian, Chen Yupeng, Liang Jing, Shi Bin, Wu Ge, Zhang Ying, Wang Dan, Li Ruifang, Yi Xia, Zhang Hua, Sun Luyang, Shang Yongfeng
Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100083, China.
Nature. 2005 Dec 15;438(7070):981-7. doi: 10.1038/nature04225.
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.
他莫昔芬是一种选择性雌激素受体调节剂，已被用于治疗激素反应性乳腺癌的各个阶段。然而，他莫昔芬在子宫中表现出部分雌激素活性，其使用与子宫内膜癌发病率的增加有关。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具有不同但重叠的靶基因谱。在重叠的靶基因中，我们鉴定出一个配对盒基因PAX2，它在子宫内膜的细胞增殖和致癌过程中起着关键作用。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未被激活，并且这种激活与PAX2启动子的癌症相关低甲基化有关。
