Androgen action is mediated through androgen receptor (AR), which appears to undergo structural and functional alterations during prostate cancer (CaP) progression. AR mutations have been infrequently reported in CaP before hormonal therapy, but in untreated, advanced tumors AR mutations are suggested to be more common. To investigate the frequency of AR mutations in aggressive CaP before hormonal therapy, we have analyzed AR coding region for aberrations in 21 paraffin-embedded prostate carcinoma samples (14 primary tumors, 7 metastases) of poor histologic differentiation. Single-stranded conformational polymorphism and sequencing analyses revealed AR missense mutations in 29% (4/14) of the primary tumors and in one (14%) metastasis. Mutations resided in the transactivation domain and in the hinge region. One of the hinge region mutants, Ser646Phe, that was identified in a patient with short endocrine therapy response, exhibited a markedly increased transcriptional activity on single androgen response element-containing promoters. In conclusion, AR mutations are frequent in high-grade CaP before initiation of hormonal therapy, and these mutations may play a role in poor therapy response and emergence of hormone-refractory CaP in some cases.

中文翻译：

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激素治疗前高级别前列腺癌的雄激素受体突变。

雄激素作用是通过雄激素受体 (AR) 介导的，雄激素受体似乎在前列腺癌 (CaP) 进展过程中发生结构和功能改变。在接受激素治疗之前，CaP 很少报道 AR 突变，但在未经治疗的晚期肿瘤中，AR 突变被认为更为常见。为了研究激素治疗前侵袭性 CaP 中 AR 突变的频率，我们分析了 21 个组织学分化差的石蜡包埋前列腺癌样本（14 个原发性肿瘤，7 个转移）中的 AR 编码区畸变。单链构象多态性和测序分析显示 29% (4/14) 的原发性肿瘤和一个 (14%) 转移瘤中存在 AR 错义突变。突变位于反式激活域和铰链区。铰链区突变体之一，Ser646Phe 是在一名内分泌治疗反应较短的患者中发现的，它在包含单个雄激素反应元件的启动子上表现出显着增加的转录活性。总之，在开始激素治疗之前，AR 突变在高级 CaP 中很常见，并且这些突变可能在某些情况下导致治疗反应不佳和激素难治性 CaP 的出现。