title: ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients.
abstract: Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.
authors.affiliation: Division of Hematology and Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Baena
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shao
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Linn
authors.forename: Kimberly
authors.initials: K
authors.lastname: Glass
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Hamblen
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Jonghwan
authors.initials: J
authors.lastname: Kim
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Godinho
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: D000728:Androgens; D002843:Chromatin; D004268:DNA-Binding Proteins; C072312:ERG protein, human; C531115:ERG protein, mouse; C095239:ETV1 protein, human; C490641:Etv1 protein, mouse; D015513:Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases