Intragenic Rearrangement and Altered RNA Splicing of the Androgen Receptor in a Cell-Based Model of Prostate Cancer Progression
Intragenic Rearrangement and Altered RNA Splicing of the Androgen Receptor in a Cell-Based Model of Prostate Cancer Progression
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DOI：
10.1158/0008-5472.can-10-1998
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Dehm, Scott M.
中科院分区：
文献类型：
--
作者：
Li, Yingming;Alsagabi, Majid;Dehm, Scott M.
雄激素耗竭治疗晚期前列腺癌(PCA)的靶点是雄激素受体(AR)的活性，AR是前列腺癌生长所需的类固醇受体转录因子。尽管雄激素持续耗竭，但致死性去势抵抗前列腺癌(CRPCa)的出现以AR的异常重新激活为标志。最近，选择性剪接被描述为一种产生COOH末端截断的、结构性活性的AR亚型的机制，可以支持CRPCA表型。然而，这些截短的AR亚型的病理来源尚不清楚。这项研究的目的是研究AR异构体活性被截断驱动的基于细胞的PCA进展模型中AR表达的变化。我们发现，在22Rv1 CRPCa细胞中，截短的AR亚型的稳定、高水平表达与大约35kb的AR基因组片段的基因内重排有关，该基因组片段含有先前描述的一组替代AR外显子。临床标本的基因组数据分析表明，在AR扩增的背景下，CRPCA发生了相关的AR基因内拷贝数变化。对22Rv1细胞的Break融合连接的克隆显示，在重排的片段两侧有长的穿插的核元件(LINE-1)，并且DNA修复特征与微同源介导的Break诱导的复制一致。这种重排是在体外前列腺癌进展过程中出现表达高水平截短AR亚型的CRPCa细胞的罕见亚群的标志。总之，这些数据提供了CRPCa中AR基因内重排的第一个报告，并与截短的AR亚型在基于细胞的PCa进展模型中的病理表达有关。巨蟹座；71(6)；2108-17。(C)2011年AACR。
Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH-terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression. Cancer Res; 71(6); 2108-17. (C) 2011 AACR.