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

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Shaw, Greg L 
Whitaker, Hayley 
Corcoran, Marie 
Dunning, Mark J 
Luxton, Hayley 

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).

Description

Keywords

Androgen receptor, Castration, Clinical trial, Gene transcription, Immunohistochemistry, Prostate cancer, Estrogen Receptor alpha, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Hormone Antagonists, Humans, Immunohistochemistry, Male, Oligopeptides, Preoperative Care, Prostate, Prostatectomy, Prostatic Neoplasms, Receptors, Androgen, Spectrum Analysis

Journal Title

European Urology

Conference Name

Journal ISSN

1421-993X
1873-7560

Volume Title

70

Publisher

Elsevier
Sponsorship
Medical Research Council (MR/L00156X/1)
Prostate Cancer UK (G2012/50)
Prostate Cancer UK (PA14-022)
We thank CRUK, The NIHR, The Academy of Medical Sciences(RG:63397) and the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (ProMPT) collaborative (G0500966/75466), Hutchison Whampoa Limited, the Human Research Tissue Bank (Addenbrooke’s Hospital, supported by the NIHR Cambridge BRC), and Cancer Research UK.