Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice
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DOI：
10.1172/jci38291
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Shaul, Philip W.
中科院分区：
文献类型：
--
作者：
Chambliss, Ken L.;Wu, Qian;Shaul, Philip W.
类固醇激素受体在细胞核中作为转录因子发挥经典功能。然而，最近的数据表明，也有类固醇激素受体的非核亚群，包括雌激素受体（ER），介导膜启动的信号传导的基础和意义尚不清楚。在这里，我们已经证明，从细胞核中排除的雌激素-树枝状聚合物缀合物（EDC）通过ER α、直接ER α-G α i相互作用和内皮NOS（eNOS）激活来刺激内皮细胞增殖和迁移。对携带雌激素反应元件荧光素酶报告基因的小鼠、小鼠子宫中的ER调节基因和eNOS酶激活的分析进一步表明，EDC特异性靶向体内非核过程。在小鼠中，雌二醇和EDC以ER α和G蛋白依赖的方式同样刺激颈动脉再内皮化，并且两种药物都减弱了内皮损伤后新生内膜增生的发展。与此相反，子宫内膜癌细胞生长在体外和子宫增大和MCF-7细胞乳腺癌异种移植生长在体内刺激雌二醇，但不EDC。因此，EDC在体内是非核选择性ER调节剂（SERM），并且在小鼠中，非核ER信号传导促进心血管保护。这些过程可能被利用来提供血管益处，而不会增加子宫癌或乳腺癌的风险。
Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ER alpha, direct ER alpha-G alpha i interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ER alpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.