Department of Electrical and Computer Engineering, Masonic Cancer Center, University of Minnesota, Twin Cities, Minnesota 55455, USA.
Cancer Res. 2011 Mar 15;71(6):2108-17. doi: 10.1158/0008-5472.CAN-10-1998. Epub 2011 Jan 19.
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.
雄激素剥夺疗法可用于治疗晚期前列腺癌（PCa），该疗法的作用靶点是雄激素受体（AR），这是一种甾体激素受体转录因子，对于 PCa 的生长是必需的。尽管持续雄激素剥夺，致命性去势抵抗性前列腺癌（CRPCa）的出现仍会导致 AR 异常重新激活。最近，人们已经发现选择性剪接是导致 COOH 端截断的、组成性激活的 AR 异构体产生的一种机制，这些异构体可以支持 CRPCa 表型。然而，这些截断的 AR 异构体的病理起源尚不清楚。本研究的目的是在一个基于细胞的 PCa 进展模型中研究 AR 表达的改变，该模型由截断的 AR 异构体活性驱动。我们发现，22Rv1 CRPCa 细胞中稳定、高水平表达截断的 AR 异构体与大约 35kb 的 AR 基因组片段的基因内重排有关，该片段包含一组先前描述的 AR 选择性外显子。对来自临床标本的基因组数据分析表明，在 AR 扩增的背景下，CRPCa 中发生了相关的 AR 基因内拷贝数改变。在 22Rv1 细胞中对断裂融合连接点进行克隆，揭示了侧翼重排片段的长散布核元件（LINE-1）和与微同源介导的断裂诱导复制一致的 DNA 修复特征。这种重排是在体外进行 PCa 进展过程中，表达高水平截断 AR 异构体的 CRPCa 细胞的罕见亚群出现的标志物。综上所述，这些数据首次报道了 CRPCa 中的 AR 基因内重排，并与基于细胞的 PCa 进展模型中截断的 AR 异构体的病理性表达有关。
