Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.

<h4>Background</h4>Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however,...

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Autores principales:	Emma Hörnberg, Erik Bovinder Ylitalo, Sead Crnalic, Henrik Antti, Pär Stattin, Anders Widmark, Anders Bergh, Pernilla Wikström
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/77576da190d54660a4133de279e53412
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spelling	oai:doaj.org-article:77576da190d54660a4133de279e534122021-11-18T06:54:57ZExpression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.1932-620310.1371/journal.pone.0019059https://doaj.org/article/77576da190d54660a4133de279e534122011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21552559/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.<h4>Methodology/principal findings</h4>Hormone-naïve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.<h4>Conclusions/significance</h4>Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.Emma HörnbergErik Bovinder YlitaloSead CrnalicHenrik AnttiPär StattinAnders WidmarkAnders BerghPernilla WikströmPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19059 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emma Hörnberg Erik Bovinder Ylitalo Sead Crnalic Henrik Antti Pär Stattin Anders Widmark Anders Bergh Pernilla Wikström Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
description	<h4>Background</h4>Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.<h4>Methodology/principal findings</h4>Hormone-naïve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.<h4>Conclusions/significance</h4>Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.
format	article
author	Emma Hörnberg Erik Bovinder Ylitalo Sead Crnalic Henrik Antti Pär Stattin Anders Widmark Anders Bergh Pernilla Wikström
author_facet	Emma Hörnberg Erik Bovinder Ylitalo Sead Crnalic Henrik Antti Pär Stattin Anders Widmark Anders Bergh Pernilla Wikström
author_sort	Emma Hörnberg
title	Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
title_short	Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
title_full	Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
title_fullStr	Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
title_full_unstemmed	Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
title_sort	expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/77576da190d54660a4133de279e53412
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Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.

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