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 Warren; David E Neal

doi:10.1016/j.eururo.2015.10.042

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 language	English
Pages (from-to)	214-218
Number of pages	5
Journal	European Urology
Volume	70
Issue number	2
Early online date	10 Nov 2015
DOIs	https://doi.org/10.1016/j.eururo.2015.10.042
Publication status	Published - Aug 2016

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The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer
Copyright 2015 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 2.01 MBLicence: CC BY

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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

@article{5f6f8ec2db1449e98ab52afbc61cb385,

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).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.",

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

year = "2016",

month = aug,

doi = "10.1016/j.eururo.2015.10.042",

language = "English",

volume = "70",

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issn = "0302-2838",

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Shaw, GL, Whitaker, H, Corcoran, M, Dunning, MJ, Luxton, H, Kay, J, Massie, CE, Miller, JL, Lamb, AD, Ross-Adams, H, Russell, R, Nelson, AW, Eldridge, MD, Lynch, AG, Ramos-Montoya, A, Mills, IG, Taylor, AE, Arlt, W, Shah, N, Warren, AY & Neal, DE 2016, 'The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer', European Urology, vol. 70, no. 2, pp. 214-218. https://doi.org/10.1016/j.eururo.2015.10.042

TY - JOUR

T1 - The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

AU - Shaw, Greg L

AU - Whitaker, Hayley

AU - Corcoran, Marie

AU - Dunning, Mark J

AU - Luxton, Hayley

AU - Kay, Jonathan

AU - Massie, Charlie E

AU - Miller, Jodi L

AU - Lamb, Alastair D

AU - Ross-Adams, Helen

AU - Russell, Roslin

AU - Nelson, Adam W

AU - Eldridge, Matthew D

AU - Lynch, Andrew G

AU - Ramos-Montoya, Antonio

AU - Mills, Ian G

AU - Taylor, Angela E

AU - Arlt, Wiebke

AU - Shah, Nimish

AU - Warren, Anne Y

AU - Neal, David E

PY - 2016/8

Y1 - 2016/8

N2 - 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.

AB - 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.

U2 - 10.1016/j.eururo.2015.10.042

DO - 10.1016/j.eururo.2015.10.042

M3 - Article

C2 - 26572708

SN - 0302-2838

VL - 70

SP - 214

EP - 218

JO - European Urology

JF - European Urology

IS - 2

ER -

The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

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