ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss

Abstract

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.

ETS fusion genes in prostate cancer

“…A model has been proposed in which ERG overexpression inhibits AR-regulated differentiation and stimulates dedifferentiation mediated by the H3K27 methyltransferase polycomb gene EZH2. In a Pten knockout GEM prostate cancer model, ERG overexpression changed the AR cistrome (Chen et al 2013).…”

“…However, in other studies, TMPRSS2-ERG GEMs did not even develop PIN. Among the progeny from crossbreeding Erg mice with Pten-knockout mice, PIN and micro-invasive cancer were observed , King et al 2009, Baena et al 2013, Chen et al 2013. Witte and colleagues provided additional evidence that ERG can cooperate with several different oncogenes or tumor suppressor genes in the development of mouse prostate tumors (Zong et al 2009).…”

Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer

“…Patients with the most common ETS gene fusion TMPRSS2-ETS related gene (TMPRSS2-ERG) have a higher incidence of metastatic disease and cancer-related death compared with fusion-negative patients (3,4), and in castration-resistant prostate cancer, TMPRSS2-ERG expression is frequently reactivated (5). In support of ERG being a key driver of prostate cancer, depletion of ERG by RNAi decreases proliferation and/or invasiveness in prostate cancer cell lines (2,6), and ectopic expression of ERG in transgenic mice was shown to promote prostate oncogenesis in cooperation with the loss of tumor suppressors (7)(8)(9)(10)(11)(12). TMPRSS2-driven overexpression of ERG controls a transcriptional network related to the development of prostate cancer and its progression to metastatic disease (13,14).…”

ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer

“…Another early event in prostate tumorigenesis is the formation of the TMPRSS2-ERG rearrangement, which fuses the transmembrane protease TMPRSS2 promoter with the coding region of the ETS transcription factor ERG (13, 14). The TMPRSS2-ERG fusion is highly prevalent in prostate cancer and is associated with disease outcome in some cases (13,15), and functionally cooperates with dysregulation of other key genes, including the PTEN tumor suppressor, in prostate cancer progression (16)(17)(18)(19). Notably, other oncogenic ETS genes (20), including ETV1, undergo translocation in prostate cancer and collaborate with PTEN in cancer progression (21-23), and at least one tumor-suppressive ETS family member, ETS2, is mutated in advanced prostate cancer (8).…”