The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

Greg L Shaw, Hayley Whitaker, Marie Corcoran, Mark J Dunning, Hayley Luxton, Jonathan Kay, Charlie E Massie, Jodi L Miller, Alastair D Lamb, Helen Ross-Adams, Roslin Russell, Adam W Nelson, Matthew D Eldridge, Andrew G Lynch, Antonio Ramos-Montoya, Ian G Mills, Angela E Taylor, Wiebke Arlt, Nimish Shah, Anne Y WarrenDavid E Neal

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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.

Original languageEnglish
Pages (from-to)214-218
Number of pages5
JournalEuropean Urology
Volume70
Issue number2
Early online date10 Nov 2015
DOIs
Publication statusPublished - Aug 2016

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    Shaw, G. L., Whitaker, H., Corcoran, M., Dunning, M. J., Luxton, H., Kay, J., Massie, C. E., Miller, J. L., Lamb, A. D., Ross-Adams, H., Russell, R., Nelson, A. W., Eldridge, M. D., Lynch, A. G., Ramos-Montoya, A., Mills, I. G., Taylor, A. E., Arlt, W., Shah, N., ... Neal, D. E. (2016). The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer. European Urology, 70(2), 214-218. https://doi.org/10.1016/j.eururo.2015.10.042