Sakamoto Takako, Eguchi Hidetaka, Omoto Yoko, Ayabe Takuya, Mori Hiroyuki, Hayashi Shin-ichi
Department of Obstetrics and Gynecology, Teikyo University School of Medicine, 2-11-1 Kaga Itabashi-ku, 173-8605, Tokyo, Japan.
Mol Cell Endocrinol. 2002 Jun 28;192(1-2):93-104. doi: 10.1016/s0303-7207(02)00086-2.
Tamoxifen is an estrogen receptor (ER)-antagonist that is widely used for the treatment of breast cancer, although it increases the risk of endometrial cancer. The mechanism mediating the stimulatory effect of tamoxifen on endometrial cancer is presently unknown. In this study we examined the effects of tamoxifen on Ishikawa 3H-12 endometrial cancer cells and MCF-7 breast cancer cells. Ishikawa cell growth was stimulated by 4-hydroxytamoxifen and accompanied by increased transcriptional activity of the endogenous ER. These stimulatory effects did not occur in MCF-7 cells. The relative transcriptional activity of the activation function (AF) 1 domain of ERalpha compared with that of the AF2 domain was 4-fold higher in Ishikawa cells than in MCF-7 cells. Mitogen-activated protein (MAP) kinase, which stimulates the transcriptional activity of AF1, was constitutively activated in Ishikawa cells, but not in MCF-7 cells. These observations suggest that the constitutively activated MAP kinase-signaling pathway in Ishikawa cells enhances the transcriptional activity of ERalpha via the AF1 domain. This ERalpha activation pathway may be involved in the stimulatory effect of tamoxifen on the development and/or progression of endometrial cancer.
他莫昔芬是一种雌激素受体（ER）拮抗剂，广泛用于治疗乳腺癌，尽管它会增加子宫内膜癌的风险。目前尚不清楚介导他莫昔芬对子宫内膜癌刺激作用的机制。在本研究中，我们检测了他莫昔芬对石川3H-12子宫内膜癌细胞和MCF-7乳腺癌细胞的影响。4-羟基他莫昔芬刺激石川细胞生长，并伴有内源性ER转录活性增加。这些刺激作用在MCF-7细胞中未出现。与AF2结构域相比，ERα激活功能（AF）1结构域在石川细胞中的相对转录活性比在MCF-7细胞中高4倍。刺激AF1转录活性的丝裂原活化蛋白（MAP）激酶在石川细胞中组成性激活，但在MCF-7细胞中未激活。这些观察结果表明，石川细胞中组成性激活的MAP激酶信号通路通过AF1结构域增强了ERα的转录活性。这种ERα激活途径可能参与了他莫昔芬对子宫内膜癌发生和/或进展的刺激作用。
