ETV1 and ERG genome binding/occupancy profiling by genome tiling array. Homo sapiens

Chromosomal rearrangements involving ETS factors, ERG and ETV1, occur frequently in prostate cancer. How these factors contribute to tumorigenesis and whether they play similar in vivo roles remain elusive. We show that ERG and ETV1 control a common transcriptional network but in an opposing fashion. In mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factors cooperated with Pten-loss, leading to localized cancer, but only ETV1 supported development of advanced adenocarcinoma, likely through enhancement of androgen receptor signaling and steroid biosynthesis. Indeed, ETV1 expression promotes autonomous testosterone production, which may contribute to tumor progression to castration-resistant prostate cancer. Patient data confirmed association of ETV1 expression with aggressive disease. We conclude that despite many shared targets, ERG and ETV1 contribute differently to prostate tumor biology. Hence, prostate cancers with these fusions should be considered as distinct subtypes for patient stratification and therapy. Overall design: Genomic targets of ERG and ETV1 transcription factors were identified by antibody-mediated and biotin-mediated ChIP-chip in human VCaP and LNCaP cells, respectively.

涉及ETS转录因子（ETS factors）ERG与ETV1的染色体重排在前列腺癌中频发出现。此类因子如何促进肿瘤发生，以及二者在体内是否发挥相似功能，目前仍不明确。本研究发现，ERG与ETV1虽可调控共同的转录网络，但二者的作用模式截然相反。在将ERG或ETV1靶向整合至内源性Tmprss2基因座的小鼠模型中，两种因子均可与PTEN缺失协同作用，引发局限性前列腺癌；但仅ETV1可支持进展性腺腺癌的发生，其机制可能为增强雄激素受体信号通路与类固醇生物合成过程。进一步研究表明，ETV1的表达可促进睾酮的自主合成，这可能推动肿瘤进展为去势抵抗性前列腺癌。患者队列数据证实，ETV1的表达与侵袭性前列腺癌密切相关。综上，尽管ERG与ETV1共享大量调控靶点，但二者对前列腺肿瘤生物学的贡献存在显著差异。因此，携带此类融合基因的前列腺癌应被视为独立亚型，用于患者分层与治疗方案选择。
实验整体设计：分别通过抗体介导与生物素介导的染色质免疫沉淀芯片（ChIP-chip）技术，在人源VCaP与LNCaP细胞系中鉴定ERG与ETV1转录因子的基因组靶标。