Molecular determinants of resistance to antiandrogen therapy
Molecular determinants of resistance to antiandrogen therapy
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DOI：
10.1038/nm972
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发表时间：
2004-01-01
期刊：
影响因子：
82.9
通讯作者：
Sawyers, CL
中科院分区：
文献类型：
--
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
使用基于微阵列的同基因前列腺癌异种移植模型，我们发现雄激素受体mRNA的适度增加是唯一与抗雄激素治疗耐药的发展相一致的变化。雄激素受体mRNA和蛋白质的这种增加是前列腺癌从激素敏感阶段转变为激素不敏感阶段的必要条件和充分条件，并且依赖于一个功能配体结合区域。雄激素受体拮抗剂在雄激素受体水平升高的细胞中表现出激动剂活性；这种拮抗剂向激动剂的转化与雄激素受体靶基因启动子招募辅助激活剂和辅助阻滞剂的变化有关。雄激素受体水平的增加通过放大低水平残留配体的信号输出和改变对拮抗剂的正常反应来增强对抗雄激素的抵抗力。这些发现为设计新的抗雄激素提供了洞察力。
Using microarray-based profiling of isogenic prostate cancer xenograft models, we found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. This increase in androgen receptor mRNA and protein was both necessary and sufficient to convert prostate cancer growth from a hormone-sensitive to a hormone-refractory stage, and was dependent on a functional ligand-binding domain. Androgen receptor antagonists showed agonistic activity in cells with increased androgen receptor levels; this antagonist-agonist conversion was associated with alterations in the recruitment of coactivators and corepressors to the promoters of androgen receptor target genes. Increased levels of androgen receptor confer resistance to antiandrogens by amplifying signal output from low levels of residual ligand, and by altering the normal response to antagonists. These findings provide insight toward the design of new antiandrogens.