Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
Department of Obstetrics and Gynecology, University of Modena and Reggio Emilia , Modena , Italy.
Front Endocrinol (Lausanne). 2014 May 26;5:80. doi: 10.3389/fendo.2014.00080. eCollection 2014.
Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor (ER) modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17β-estradiol (E2) on T47-D ER+ breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, re-distribution of actin fibers toward the cell membrane was observed. However, when E4 was added to E2, an inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin-radixin-moesin family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr(558), which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of estrogen receptor-α. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring ER modulator in the breast.
雌三醇（E4）是一种天然存在的人类雌激素，在怀孕期间浓度很高。由于其口服生物利用度高和血浆半衰期长，E4 特别适合治疗应用。E4 作为一种选择性雌激素受体（ER）调节剂，对子宫内膜或中枢神经系统发挥雌激素作用，同时拮抗雌二醇在乳房中的作用。我们测试了 E4 单独或与 17β-雌二醇（E2）一起对 T47-D ER+乳腺癌细胞在三维基质中的迁移和侵袭的影响。E4 给药于 T47-D 细胞可弱刺激迁移和侵袭。然而，E4 降低了 E2 诱导的运动和侵袭的程度。乳腺癌细胞的运动需要肌动蛋白细胞骨架的重塑。在暴露于 E4 时，观察到肌动蛋白纤维向细胞膜的弱、浓度依赖性重新分布。然而，当 E4 添加到 E2 时，观察到 E2 诱导的肌动蛋白重塑的抑制。雌激素通过 ezrin-radixin-moesin 家族的肌动蛋白调节蛋白刺激 ER+乳腺癌细胞的运动，诱导肌动蛋白和细胞膜重塑。E4 是 moesin 磷酸化 Thr(558)的弱诱导剂，这解释了其功能激活。在与 E2 的共同处理中，E4 以浓度相关的方式阻断了该肌动蛋白控制器的激活。这些作用是通过雌激素受体-α的募集获得的。总之，E4 作为一种弱雌激素作用于乳腺癌细胞细胞骨架重塑和运动。然而，当 E2 存在时，E4 拮抗了 E2 的刺激作用。这有助于形成一个新的假说，即 E4 可能是乳腺中天然存在的 ER 调节剂。
