Abstract 5393: ETV1 directs androgen metabolism and confers aggressive prostate cancer in engineered mice and patients.
Authors: Baena Esther , Shao Zhen , Linn Douglas , Glass Kimberly , Hamblen Melanie , Fujiwara Yuko , Kim Jonghwan , Nguyen Minh , Zhang Xin , Godinho Frank , Bronson Roderick T. , Mucci Lorelei , Loda Massimo , Yuan Guocheng , Li Zhe , Orkin Stuart H. 
Published: August 2014

A central challenge in prostate cancer is identification of those men with prostate cancer whose disease will eventually progress to the lethal castration-resistant stage. Understanding molecular events leading to castration-resistant prostate cancer (CRPC), and identifying new disease markers are critical for the development of improved therapies for such patients. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer (PCa). It is widely presumed that ectopically expressed ETV1 (mainly due to gene fusions) plays a similar role in prostate tumorigenesis to that of ERG. However, we found that high levels of ETV1 expression are often associated with more advanced PCa in patient cohorts tested, whereas ERG overexpression is mainly associated with localized PCa and with elevated androgen receptor (AR) signaling. These data suggest that ETV1 and ERG may play different roles in prostate tumorigenesis. To address this question, we have generated Tmprss2-ERG (T-ERG) and Tmprss2-ETV1 (T-ETV1) knockin mouse models, targeting the two most prevalent ETS family members involved in fusions in PCa. Although, male mice carrying ERG or ETV1 targeted to the endogenous Tmprss2 locus alone are normal, either factor cooperated with Pten-loss, leading to localized cancer. Interestingly, only ETV1 supported development of advanced adenocarcinoma under Pten-loss background. To learn the molecular insights underlying this difference, we then focused mechanistic studies on the identification of chromosomal targets directly bound by ERG and ETV1. We showed that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the AR transcriptional program, ETV1 cooperates with AR signaling by favoring its activation. Then, we performed microarray gene expression profiling for mouse prostate epithelial cells carrying T-ETV1 knockin allele alone. Strikingly, by gene set enrichment analysis, we found in T-ETV1 prostate cells (compared to controls), most top enriched gene sets from the KEGG pathway database are related to steroid and cholesterol biosynthesis. Consistent with this, when we castrated T-ETV1 knockin males, we found a significant portion of ETV1 expressing prostate cells (tracked by GFP expression) could survive castration long-term. Moreover, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. These data suggest that ETV1 may reprogram metabolism toward steroid synthesis, which may promote progression to castration-resistant state. Lastly, patient data confirmed association of ETV1 expression and androgen metabolism. Thus, the distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to the underlying programs controlled by ETV1.

Citation Format: Esther Baena, Zhen Shao, Douglas Linn, Kimberly Glass, Melanie Hamblen, Yuko Fujiwara, Jonghwan Kim, Minh Nguyen, Xin Zhang, Frank Godinho, Roderick T. Bronson, Lorelei Mucci, Massimo Loda, Guocheng Yuan, Zhe Li, Stuart H. Orkin. ETV1 directs androgen metabolism and confers aggressive prostate cancer in engineered mice and patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2013-5393