在晚期前列腺癌中检测到的突变雄激素受体被肾上腺雄激素和孕激素激活。
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Culig Z, Hobisch A, Cronauer MV, Cato AC, Hittmair A, Radmayr C, Eberle J, Bartsch G, Klocker H
在晚期前列腺癌中检测到的突变雄激素受体被肾上腺雄激素和孕激素激活。
Mol Endocrinol. 1993 Dec;7(12):1541-50。
- PubMed ID
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8145761 (在PubMed］
- 摘要
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雄激素受体(AR)的结构变化可能有助于前列腺癌对内分泌治疗产生耐药性。我们从7例晚期转移性前列腺肿瘤患者的肿瘤标本中分离出AR cDNA片段。在一个对内分泌和细胞毒性治疗无效的患者的标本中，我们检测到该受体的激素结合区域有一个点突变。AR突变是在核苷酸2671上发生的鸟嘌呤到腺嘌呤的转变，导致715位的野生型缬氨酸被蛋氨酸取代。这是一个体细胞突变，因为它不存在于从同一患者的前列腺和睾丸组织分离的AR基因组DNA片段中。突变AR在表达载体中被重新构建，并在COS-7和CV-1细胞中瞬时表达。激素结合试验显示，突变型受体与野生型受体结合雄激素的能力并无差异。合成雄激素米波隆对两种受体的解离常数均为3nm。竞争结合试验显示，其他类固醇和非甾体抗雄激素的结合也没有显著差异。然而，为了确定突变受体的反式激活电位，转染实验产生了该受体与野生型受体的作用差异。 Dihydrotestosterone and the synthetic androgens methyltrienolone (R1881) and mibolerone were equally proficient in conferring trans-activation activity to both the mutant and wild type receptors. Adrenal androgens such as dehydroepiandrosterone and androstenedione, as well as progesterone mediated a higher trans-activation through the mutant than through the wild type receptor. These data demonstrate that the exchange of a single valine into methionine at position 715 in the AR promoters trans-activation not only by testicular but also by adrenal androgens and progesterone. This pattern of ligand-dependent trans-activation may have significance in the process controlling the progression of prostatic carcinoma.