Wang Zhuo, Kyo Satoru, Maida Yoshiko, Takakura Masahiro, Tanaka Masaaki, Yatabe Noriyuki, Kanaya Taro, Nakamura Mitsuhiro, Koike Koji, Hisamoto Koji, Ohmichi Masahide, Inoue Masaki
Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
Oncogene. 2002 May 16;21(22):3517-24. doi: 10.1038/sj.onc.1205463.
Tamoxifen is widely applied as an antiestrogenic agent for adjuvant therapy in the treatment of breast cancer, while its estrogen-agonistic activity occasionally causes proliferative disorders or carcinogenesis at other sites, such as the uterus. We reported that estrogen activates telomerase in breast and endometrial cancer cells. The present study examines the effects of tamoxifen on the gene expression of human telomerase reverse transcriptase (hTERT) in breast and endometrial cancer cells. Tamoxifen inhibited the cell growth of MCF-7 cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects. In contrast, tamoxifen stimulated the growth of Ishikawa cells and activated hTERT mRNA expression in the absence or presence of E2, exhibiting estrogen-agonistic action. Transient expression assays revealed that these actions of tamoxifen are achieved by transcriptional regulation of the hTERT promoter. An estrogen responsive element (ERE) in the hTERT 5' regulatory region was partly responsible for both the E2-antagonistic and -agonistic actions of tamoxifen. Tamoxifen activated the MAP kinase cascade in Ishikawa cells, but not in MCF-7 cells, and the activation of hTERT mRNA expression was effectively blocked by MEK inhibitor, suggesting that the MAP kinase pathway is involved in the tamoxifen-induced activation of hTERT. These findings indicate that tamoxifen regulates hTERT expression in a cell-type specific manner. Tamoxifen-induced activation of hTERT may be one component of estrogen agonistic function of tamoxifen that is involved in endometrial carcinogenesis induced by this agent.
他莫昔芬作为一种抗雌激素药物被广泛应用于乳腺癌的辅助治疗，然而其雌激素激动活性偶尔会在其他部位引发增殖性疾病或致癌作用，比如子宫。我们曾报道雌激素可激活乳腺癌和子宫内膜癌细胞中的端粒酶。本研究检测了他莫昔芬对人端粒酶逆转录酶（hTERT）在乳腺癌和子宫内膜癌细胞中基因表达的影响。他莫昔芬抑制了MCF-7细胞的生长，以及在雌激素（E2）存在时hTERT mRNA的表达，拮抗了E2的作用。相反，他莫昔芬在E2不存在或存在的情况下刺激了Ishikawa细胞的生长并激活了hTERT mRNA的表达，表现出雌激素激动作用。瞬时表达分析表明，他莫昔芬的这些作用是通过对hTERT启动子的转录调控实现的。hTERT 5'调控区域中的雌激素反应元件（ERE）部分地介导了他莫昔芬的E2拮抗和激动作用。他莫昔芬激活了Ishikawa细胞中的MAP激酶级联反应，但未激活MCF-7细胞中的该反应，并且hTERT mRNA表达的激活被MEK抑制剂有效阻断，这表明MAP激酶途径参与了他莫昔芬诱导的hTERT激活。这些发现表明他莫昔芬以细胞类型特异性的方式调节hTERT的表达。他莫昔芬诱导的hTERT激活可能是他莫昔芬雌激素激动功能的一个组成部分，该功能参与了由该药物诱导的子宫内膜癌发生。
