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Eur Urol. 2016 Aug;70(2):214-8. doi: 10.1016/j.eururo.2015.10.042. Epub 2015 Nov 10.

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer.

Author information

1
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.
2
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; University College London, London, UK.
3
Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
4
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
5
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Department of Urology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
6
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.
7
Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Egbaston, Birmingham, UK.
8
Department of Pathology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
9
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.

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).

PATIENT SUMMARY:

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.

KEYWORDS:

Androgen receptor; Castration; Clinical trial; Gene transcription; Immunohistochemistry; Prostate cancer

PMID:
26572708
PMCID:
PMC4926724
DOI:
10.1016/j.eururo.2015.10.042
[Indexed for MEDLINE]
Free PMC Article

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