ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss.
复制标题
作者：
由于缺乏合适的实验系统，ets介导的前列腺癌发生的研究一直受到阻碍。在这里，我们描述了一种新的条件小鼠模型，它在整个前列腺中提供了稳健、均匀的ERG表达。当纯合子Pten缺失时，小鼠发展为加速的、高渗透的侵袭性前列腺癌。在小鼠前列腺组织中，ERG显著增加雄激素受体（AR）结合。仅在Pten缺失的情况下，观察到强大的ergg介导的转录变化，包括AR转录输出和参与细胞死亡、迁移、炎症和血管生成的基因的恢复。类似地，ETV1在ETV1易位、pten缺失的人前列腺癌细胞中正调控AR细胞和转录输出。在两个大型临床队列中，在pten阴性的前列腺癌标本中，ERG和ETV1的表达与更高的AR转录输出相关。我们认为，ETS因子通过改变AR细胞，激活前列腺上皮对异常上游信号（如PTEN丢失）做出反应，从而引起前列腺特异性转化。
Studies of ETS-mediated prostate oncogenesis have been hampered by the lack of suitable experimental systems. Here we describe a new conditional mouse model which gives robust, homogenous ERG expression throughout the prostate. When combined with homozygous Pten loss, mice developed accelerated, highly penetrant invasive prostate cancer. In mouse prostate tissue, ERG significantly increased androgen receptor (AR) binding. Robust ERG-mediated transcriptional changes, observed only in the setting of Pten loss, included restoration of AR transcriptional outut and genes involved in cell death, migration, inflammation and angiogenesis. Similarly, ETV1 positively regulated AR cistrome and transcriptional output in ETV1-translocated, PTEN-deficient human prostate cancer cells. In two large clinical cohorts, ERG and ETV1 expression correlated with higher AR transcriptional output in PTEN-negative prostate cancer specimens. We propose that ETS factors cause prostate-specific transformation by altering the AR cistrome, priming the prostate epithelium to respond to aberrant upstream signals such as PTEN loss.
登录
查看更多内容
影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
5.3
作者：
Andreu-Vieyra, Claudia;Lai, John;Coetzee, Gerhard A.
通讯作者：
Coetzee, Gerhard A.
影响因子：
30.8
作者：
King, Jennifer C.;Xu, Jin;Wongvipat, John;Hieronymus, Haley;Carver, Brett S.;Leung, David H.;Taylor, Barry S.;Sander, Chris;Cardiff, Robert D.;Couto, Suzana S.;Gerald, William L.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK