title: ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.
abstract: To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.forename: Samprit
authors.initials: S
authors.lastname: Banerjee
authors.forename: Yihang
authors.initials: Y
authors.lastname: Pan
authors.forename: Jindan
authors.initials: J
authors.lastname: Yu
authors.forename: Terry
authors.initials: T
authors.lastname: Vuong
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lafargue
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Mertz
authors.forename: Sunita R
authors.initials: SR
authors.lastname: Setlur
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
mesh_terms: D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D009376:Neoplasms, Hormone-Dependent; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D000071165:Trefoil Factor-3
chemical_list: C072312:ERG protein, human; D010455:Peptides; D011944:Receptors, Androgen; C082495:TFF3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D000071165:Trefoil Factor-3