Muldoon T G
Ann N Y Acad Sci. 1986;464:17-36. doi: 10.1111/j.1749-6632.1986.tb15990.x.
The studies described herein are focused on the nature and regulation of estrogen receptors in normal mammary tissue, with the rationale that manipulation of these receptors is the sole basis for endocrine therapy of human breast cancer. Various features of this complex system have been uncovered by our studies. The presence of different forms of cytosol estrogen receptor, fluctuating in unison with glandular stimulation, results in differential responsiveness of the cells. Tissue that is relatively estrogen-starved presents its receptors in a form that avidly attract the limited available ligands and can hastily put them to use in the nucleus. In contrast, the receptor system in the highly stimulated state displays a sort of refractoriness to estrogen, being relatively sluggish in its responsiveness. Once formed, however, these latter complexes are probably far more effective in terms of eliciting estrogenic responses, since they have an enhanced affinity for DNA and a prolonged half-life. (Table; see text) Prolactin is clearly a very important mediator of the action of estrogen on the mammary gland estrogen receptors, presenting a tissue-specific difference in comparison with the regulation of the uterine estrogen-receptor system. An odd finding was that prolactin inhibits nuclear retention of the estrogen receptor (and probably the progesterone receptor), an effect that is counterproductive to its very strong positive action on the level of intracellular receptor. Perhaps prolactin is the gross effector of receptor fluctuation, allowing estrogen the privilege of dictating the degree of receptor function; indeed our data on the dose-responsiveness of estrogen action and the effects of bromocriptine indicate that a portion of the estrogenic stimulation is not mediated by prolactin. An interesting sidelight of these studies was the finding that high levels of bromocriptine, pharmacologic in terms of prolactin suppression, exhibited an inhibitory effect on nuclear retention of estrogen receptors that was independent of, and did not prevent subsequent elicitation of, the action of prolactin on the receptors. The role of prolactin in tumorigenesis is well established in experimental animals, but its role in the human disease is not clear. Although prolactin receptors have been measured in human breast cancer, there does not appear to be any distinguishable correlation with the presence of estrogen or progesterone receptors. While it is a bit premature to draw conclusions, initial trials of bromocriptine usage have not been supportive of beneficial effects of such treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
本文所述的研究聚焦于正常乳腺组织中雌激素受体的性质和调节，其理论依据是对这些受体的操控是人类乳腺癌内分泌治疗的唯一基础。我们的研究揭示了这个复杂系统的各种特征。不同形式的胞质雌激素受体的存在，与腺体刺激同步波动，导致细胞产生不同的反应。相对缺乏雌激素的组织，其受体呈现出一种形式，能强烈吸引有限的可用配体，并能迅速将它们用于细胞核中。相反，处于高度刺激状态的受体系统对雌激素表现出一种不应性，其反应相对迟缓。然而，一旦形成，这些后期形成的复合物在引发雌激素反应方面可能更有效，因为它们对DNA的亲和力增强，半衰期延长。（表格；见正文）催乳素显然是雌激素作用于乳腺雌激素受体的一个非常重要的介质，与子宫雌激素受体系统的调节相比，存在组织特异性差异。一个奇怪的发现是，催乳素会抑制雌激素受体（可能还有孕激素受体）在细胞核中的滞留，这一作用与其对细胞内受体水平的非常强的正向作用适得其反。也许催乳素是受体波动的总体效应器，赋予雌激素决定受体功能程度的特权；事实上，我们关于雌激素作用的剂量反应性和溴隐亭作用的数据表明，一部分雌激素刺激不是由催乳素介导的。这些研究的一个有趣的附带发现是，高剂量的溴隐亭，就抑制催乳素而言具有药理作用，对雌激素受体在细胞核中的滞留表现出抑制作用，这种作用独立于催乳素对受体的作用，且不会阻止随后催乳素对受体作用的引发。催乳素在实验动物肿瘤发生中的作用已得到充分证实，但其在人类疾病中的作用尚不清楚。虽然在人类乳腺癌中已检测到催乳素受体，但与雌激素或孕激素受体的存在似乎没有任何明显的相关性。虽然现在得出结论还为时过早，但溴隐亭使用的初步试验并不支持这种治疗有有益效果。（摘要截选至400字）
