Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.

<h4>Background</h4>Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how...

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Autores principales:	Rute B Marques, Natasja F Dits, Sigrun Erkens-Schulze, Wytske M van Weerden, Guido Jenster
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/23e2616e34464feaac35cb0715fc130a
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spelling	oai:doaj.org-article:23e2616e34464feaac35cb0715fc130a2021-11-18T07:03:07ZBypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.1932-620310.1371/journal.pone.0013500https://doaj.org/article/23e2616e34464feaac35cb0715fc130a2010-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20976069/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.<h4>Methodology/principal findings</h4>Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.<h4>Conclusions/significance</h4>Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.Rute B MarquesNatasja F DitsSigrun Erkens-SchulzeWytske M van WeerdenGuido JensterPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 10, p e13500 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wytske M van Weerden Guido Jenster Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
description	<h4>Background</h4>Prostate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.<h4>Methodology/principal findings</h4>Microarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10(-7)). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.<h4>Conclusions/significance</h4>Therapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.
format	article
author	Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wytske M van Weerden Guido Jenster
author_facet	Rute B Marques Natasja F Dits Sigrun Erkens-Schulze Wytske M van Weerden Guido Jenster
author_sort	Rute B Marques
title	Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
title_short	Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
title_full	Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
title_fullStr	Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
title_full_unstemmed	Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
title_sort	bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/23e2616e34464feaac35cb0715fc130a
work_keys_str_mv	AT rutebmarques bypassmechanismsoftheandrogenreceptorpathwayintherapyresistantprostatecancercellmodels AT natasjafdits bypassmechanismsoftheandrogenreceptorpathwayintherapyresistantprostatecancercellmodels AT sigrunerkensschulze bypassmechanismsoftheandrogenreceptorpathwayintherapyresistantprostatecancercellmodels AT wytskemvanweerden bypassmechanismsoftheandrogenreceptorpathwayintherapyresistantprostatecancercellmodels AT guidojenster bypassmechanismsoftheandrogenreceptorpathwayintherapyresistantprostatecancercellmodels
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Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models.

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