title: SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer.
abstract: OBJECTIVE
  The neuroendocrine phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the neuroendocrine phenotype in CRPC.
  
  
  METHODS
  Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by IHC in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole-genome microarrays. REST splicing was verified by PCR.
  
  
  RESULTS
  Coexpression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR(+)/PSA(+) (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR(-)/PSA(-). By IHC, of the 71 metastases analyzed by whole-genome microarrays, 5 metastases were CHGA(+)/SYP(+)/AR(-), and 5 were CHGA(+)/SYP(+)/AR(+). Only CHGA(+)/SYP(+) metastases had a neuroendocrine transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the neuroendocrine signature in CHGA(+)/SYP(+) metastases and all CHGA(+)/SYP(+) LuCaP xenografts. In addition, expression of SRRM4 in LuCaP neuroendocrine xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain.
  
  
  CONCLUSIONS
  (i) Metastatic neuroendocrine status can be heterogeneous in the same patient, (ii) the CRPC neuroendocrine molecular phenotype can be defined by CHGA(+)/SYP(+) dual positivity, (iii) the neuroendocrine phenotype is not necessarily associated with the loss of AR activity, and (iv) the splicing of REST by SRRM4 could promote the neuroendocrine phenotype in CRPC.
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ilsa M
authors.initials: IM
authors.lastname: Coleman
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Lisha G
authors.initials: LG
authors.lastname: Brown
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Lori
authors.initials: L
authors.lastname: Kollath
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Hung-Ming
authors.initials: HM
authors.lastname: Lam
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ruth
authors.initials: R
authors.lastname: Dumpit
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Lisly
authors.initials: L
authors.lastname: Chéry
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Bryce
authors.initials: B
authors.lastname: Lakely
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Martine
authors.initials: M
authors.lastname: Roudier
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington. Department of Veterans Affairs Medical Center, Seattle, Washington.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.affiliation: Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington. Department of Veterans Affairs Medical Center, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington. cmorriss@u.washington.edu.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
mesh_terms: D053379:Chromogranin A / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055099:Neuroendocrine Cells / Q000378:metabolism*; D010641:Phenotype; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology*; D012326:RNA Splicing / Q000502:physiology; D011944:Receptors, Androgen / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D053379:Chromogranin A; D009419:Nerve Tissue Proteins; D017430:Prostate-Specific Antigen; D011944:Receptors, Androgen; D012097:Repressor Proteins; D016708:Synaptophysin; D000099229:RE1-Silencing Transcription Factor; C000595377:SRRM4 protein, human