Murphy C S, Jordan V C
Department of Human Oncology, University of Wisconsin-Madison 53792.
Receptor. 1990;1(1-2):65-82.
The identification and isolation of a soluble estrogen receptor protein from estrogen target tissues, e.g., uterus, more than 25 years ago provided a unique opportunity for the biochemical pharmacologist to study the interaction of agonist and antagonist molecules in a well-defined organ. Nonsteroidal antiestrogens have proved to be valuable research tools to study cell replication or estrogen specific protein synthesis, e.g., prolactin synthesis or progesterone receptor induction. During the past two decades the antiestrogen tamoxifen has become the endocrine treatment of choice for all stages of breast cancer. This fact has provided an additional incentive to study breast cancer cell replication. In the laboratory breast cancer cells can be used to study the direct actions of antiestrogens without the complicating aspects of pharmacokinetics and metabolism. Studies of the structure-activity relationships of antiestrogens compliment the current investigation of steroid hormone receptors as part of a superfamily of transcription factors. Antiestrogens will, in the future, provide valuable information (from X-ray crystallography) about the three-dimensional folding required if a steroid receptor complex is to prevent cell replication. Clearly this information, and the description of additional transcription factors in hormone-independent cells may prove to be critical for the development of new therapeutic opportunities.
25年多前，从雌激素靶组织（如子宫）中鉴定和分离出可溶性雌激素受体蛋白，为生化药理学家提供了一个独特的机会，使其能够在一个明确界定的器官中研究激动剂和拮抗剂分子之间的相互作用。非甾体类抗雌激素已被证明是研究细胞复制或雌激素特异性蛋白质合成（如催乳素合成或孕酮受体诱导）的有价值的研究工具。在过去的二十年中，抗雌激素他莫昔芬已成为乳腺癌各阶段内分泌治疗的首选药物。这一事实为研究乳腺癌细胞复制提供了额外的动力。在实验室中，乳腺癌细胞可用于研究抗雌激素的直接作用，而无需考虑药代动力学和代谢等复杂因素。抗雌激素结构 - 活性关系的研究补充了当前对作为转录因子超家族一部分的类固醇激素受体的研究。未来，抗雌激素将（通过X射线晶体学）提供有关如果类固醇受体复合物要阻止细胞复制所需的三维折叠的有价值信息。显然，这些信息以及对激素非依赖性细胞中其他转录因子的描述可能对开发新的治疗机会至关重要。
