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Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses
Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mix...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127155/ https://www.ncbi.nlm.nih.gov/pubmed/30190514 http://dx.doi.org/10.1038/s41467-018-06067-7 |
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author | Li, Qiuhui Deng, Qu Chao, Hsueh-Ping Liu, Xin Lu, Yue Lin, Kevin Liu, Bigang Tang, Gregory W. Zhang, Dingxiao Tracz, Amanda Jeter, Collene Rycaj, Kiera Calhoun-Davis, Tammy Huang, Jiaoti Rubin, Mark A. Beltran, Himisha Shen, Jianjun Chatta, Gurkamal Puzanov, Igor Mohler, James L. Wang, Jianmin Zhao, Ruizhe Kirk, Jason Chen, Xin Tang, Dean G. |
author_facet | Li, Qiuhui Deng, Qu Chao, Hsueh-Ping Liu, Xin Lu, Yue Lin, Kevin Liu, Bigang Tang, Gregory W. Zhang, Dingxiao Tracz, Amanda Jeter, Collene Rycaj, Kiera Calhoun-Davis, Tammy Huang, Jiaoti Rubin, Mark A. Beltran, Himisha Shen, Jianjun Chatta, Gurkamal Puzanov, Igor Mohler, James L. Wang, Jianmin Zhao, Ruizhe Kirk, Jason Chen, Xin Tang, Dean G. |
author_sort | Li, Qiuhui |
collection | PubMed |
description | Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR(−/lo)). Xenograft modeling demonstrates that AR(+) CRPC is enzalutamide-sensitive but AR(−/lo) CRPC is resistant. Genome editing-derived AR(+) and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR(+/hi) and AR(−/lo) CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR(−/lo) PCa cells/clones. |
format | Online Article Text |
id | pubmed-6127155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61271552018-09-10 Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses Li, Qiuhui Deng, Qu Chao, Hsueh-Ping Liu, Xin Lu, Yue Lin, Kevin Liu, Bigang Tang, Gregory W. Zhang, Dingxiao Tracz, Amanda Jeter, Collene Rycaj, Kiera Calhoun-Davis, Tammy Huang, Jiaoti Rubin, Mark A. Beltran, Himisha Shen, Jianjun Chatta, Gurkamal Puzanov, Igor Mohler, James L. Wang, Jianmin Zhao, Ruizhe Kirk, Jason Chen, Xin Tang, Dean G. Nat Commun Article Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR(−/lo)). Xenograft modeling demonstrates that AR(+) CRPC is enzalutamide-sensitive but AR(−/lo) CRPC is resistant. Genome editing-derived AR(+) and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR(+/hi) and AR(−/lo) CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR(−/lo) PCa cells/clones. Nature Publishing Group UK 2018-09-06 /pmc/articles/PMC6127155/ /pubmed/30190514 http://dx.doi.org/10.1038/s41467-018-06067-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Li, Qiuhui Deng, Qu Chao, Hsueh-Ping Liu, Xin Lu, Yue Lin, Kevin Liu, Bigang Tang, Gregory W. Zhang, Dingxiao Tracz, Amanda Jeter, Collene Rycaj, Kiera Calhoun-Davis, Tammy Huang, Jiaoti Rubin, Mark A. Beltran, Himisha Shen, Jianjun Chatta, Gurkamal Puzanov, Igor Mohler, James L. Wang, Jianmin Zhao, Ruizhe Kirk, Jason Chen, Xin Tang, Dean G. Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title | Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title_full | Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title_fullStr | Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title_full_unstemmed | Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title_short | Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses |
title_sort | linking prostate cancer cell ar heterogeneity to distinct castration and enzalutamide responses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127155/ https://www.ncbi.nlm.nih.gov/pubmed/30190514 http://dx.doi.org/10.1038/s41467-018-06067-7 |
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