title: The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.
abstract: The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of α-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).
  
  
  
  This first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK; University College Hospitals NHS Trust, UK. Electronic address: gregshaw@doctors.org.uk.
authors.forename: Greg L
authors.initials: GL
authors.lastname: Shaw
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; University College London, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Whitaker
authors.affiliation: Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Marie
authors.initials: M
authors.lastname: Corcoran
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dunning
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; University College London, London, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Luxton
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; University College London, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kay
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Charlie E
authors.initials: CE
authors.lastname: Massie
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Lamb
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ross-Adams
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Nelson
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Eldridge
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Lynch
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ramos-Montoya
authors.affiliation: Prostate Cancer Research Group, Nordic EMBL Partnership, Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway; Departments of Cancer Prevention and Urology, Institute of Cancer Research and Oslo University Hospitals, Oslo, Norway; Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer Research, Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Egbaston, Birmingham, UK.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Egbaston, Birmingham, UK.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.affiliation: Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Nimish
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Pathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Warren
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK; Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
mesh_terms: D047628:Estrogen Receptor alpha / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage*; D011300:Preoperative Care; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D011944:Receptors, Androgen / Q000378:metabolism*; D013057:Spectrum Analysis / Q000379:methods
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006727:Hormone Antagonists; D009842:Oligopeptides; D011944:Receptors, Androgen; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide
keywords: Androgen receptor; Castration; Clinical trial; Gene transcription; Immunohistochemistry; Prostate cancer