Functional characterization of mutant androgen receptors from androgen-independent prostate cancer.
Functional characterization of mutant androgen receptors from androgen-independent prostate cancer.
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发表时间：
1997-08
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通讯作者：
M. Fenton;T. Shuster;A. M. Fertig;M. Taplin;G. Kolvenbag;G. Bubley;S. Balk
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作者：
M. Fenton;T. Shuster;A. M. Fertig;M. Taplin;G. Kolvenbag;G. Bubley;S. Balk
在一系列雄激素非依赖性前列腺癌中发现了雄激素受体（AR）突变，其改变了类固醇激素的特异性。为了解决这些突变AR的功能特性，可能有助于他们在体内的选择，一系列的类固醇激素和抗雄激素的反应进行了评估。CV-1细胞共转染野生型或突变AR和荧光素酶报告质粒调节雄激素反应元件。分析了5 α-二氢睾酮（正常前列腺中最活跃的雄激素）和雄烯二酮（一种来自肾上腺的主要雄激素）的剂量-反应曲线。虽然突变AR对这两种类固醇都有反应，但反应相当于或低于野生型AR。相反，对野生型AR的竞争性拮抗剂氟替卡松的反应通过三种突变显著增加。第二种抗雄激素药物尼鲁米特也观察到类似的反应。比卡鲁胺（另一种与氟氯噻嗪相关的抗雄激素药）仍然是这些突变AR的拮抗剂。最后，在该系统中观察到氟替卡松是野生型AR的弱部分激动剂。这些结果表明，与雄激素消融治疗前列腺癌联合使用的氟替卡松可能会选择具有氟替卡松诱导AR的肿瘤细胞。
Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.