培训资料--乳腺癌的辅助内分泌.ppt

* ER在氨基端和羧基端各有一个转录激活域，AF1和AF2，配体依赖性的AF1和配体非依赖性的AF2各自独立或相互协同发挥计划作用 ERE：雌激素反应元件 Eralfa能够通过经典的ERE途径活化基因转录。雌激素如雌二醇弥散于核中与Eralfa结合，雌激素结合的ER异构体变换空间构象导致其于Hsp90的分离，加上协同活化因子的作用使单体二聚化，促进ER的DNA结合区与靶基因上雌激素反应元件结合，启动转录机制，调控基因表达。 A schematic representation of the effect of the full agonist estradiol (E) on the estrogen receptor (ER) leading to full activation of DNA transcription The full agonist, estradiol, binds to the estrogen receptor in the cell cytoplasm The estrogen-ER complex has two activation functions, AF1 and AF2 The complex dimerizes and localizes to the cell nucleus, where it binds to the estrogen response element (ERE) of DNA Coactivators are recruited by the activation functions This leads to stimulation of activity of RNA polymerase II (RNA POL II) In breast cancer cells, transcription of estradiol-responsive genes leads ultimately to tumor growth * 他莫昔芬可以竞争性的和ER的激素结合区结合，形成激素受体复合物，引起ER构象改变，使DNA结合区不能暴露，无法与靶基因的ERE结合，从而抑制转录 A schematic representation comparing the action of tamoxifen (T) with ICI 182,780 (F) leading to no transcription The ICI 182,780-ER complex forms in which neither of the activation functions is active The complex does not dimerize and localization to the cell nucleus is markedly reduced No coactivators are recruited No stimulation of transcription occurs and no estrogen-dependent cell division takes place In addition, the ICI 182,780 complex rapidly degrades, resulting in a loss of ER protein. The outcome is known as downregulation of ER 氟维司群和肿瘤细胞膜上的ER结合成F-ER复合物，在氟维司群作用下，复合物中的ER蛋白丢失，ER上主要功能基团失活，影响了ER与DNA结合，从而使DNA转录受抑制，肿瘤细胞不能正常复制 本品是一类新的ER抑制剂—ER下调剂类乳腺癌治疗药物。由于在许多乳腺癌患者中均发现有ER，且这些肿瘤的生长受到雌激素的刺激，因此目前治疗乳腺癌的主要方法是减少雌激素的浓度。本品可与ER竞争性结合，其亲和力可与雌二醇相比。本品还可阻断ER，抑制其与雌激素的结合，并激发受体发生形态改变，降低ER浓度从而使肿瘤细胞受到损害。这种通过ER的作用与Ki67的减少有关，而后者是一种细胞增生标志物。 * represents the first in a new class of drugs that bind, block and degrade ER, an Estrogen Receptor Downregulator * 在由胆固醇转化为人体所需的激素（盐皮质激素、性激素和糖皮质激素）和由雄激素转化为雌激素的过程中， 非选择性芳香化酶抑制剂作用于激素产生的各个环节，虽然抑制了雌激素的产生，但其他激素的产生也受到影响，会引起很多副作用