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Secreted indicators of androgen receptor activity in breast cancer pre-clinical models
PURPOSE: Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimal...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567567/ https://www.ncbi.nlm.nih.gov/pubmed/34736512 http://dx.doi.org/10.1186/s13058-021-01478-9 |
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author | Hanamura, Toru Christenson, Jessica L. O’Neill, Kathleen I. Rosas, Emmanuel Spoelstra, Nicole S. Williams, Michelle M. Richer, Jennifer K. |
author_facet | Hanamura, Toru Christenson, Jessica L. O’Neill, Kathleen I. Rosas, Emmanuel Spoelstra, Nicole S. Williams, Michelle M. Richer, Jennifer K. |
author_sort | Hanamura, Toru |
collection | PubMed |
description | PURPOSE: Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity. METHODS: Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype. RESULTS: Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes. CONCLUSION: KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01478-9. |
format | Online Article Text |
id | pubmed-8567567 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-85675672021-11-04 Secreted indicators of androgen receptor activity in breast cancer pre-clinical models Hanamura, Toru Christenson, Jessica L. O’Neill, Kathleen I. Rosas, Emmanuel Spoelstra, Nicole S. Williams, Michelle M. Richer, Jennifer K. Breast Cancer Res Research Article PURPOSE: Accumulating evidence has attracted attention to the androgen receptor (AR) as a biomarker and therapeutic target in breast cancer. We hypothesized that AR activity within the tumor has clinical implications and investigated whether androgen responsive serum factors might serve as a minimally invasive indicator of tumor AR activity. METHODS: Based on a comprehensive gene expression analysis of an AR-positive, triple negative breast cancer patient-derived xenograft (PDX) model, 163 dihydrotestosterone (DHT)-responsive genes were defined as an androgen responsive gene set. Among them, we focused on genes that were DHT-responsive that encode secreted proteins, namely KLK3, AZGP1 and PIP, that encode the secreted factors prostate specific antigen (PSA), zinc-alpha-2-glycoprotein (ZAG) and prolactin induced protein (PIP), respectively. Using AR-positive breast cancer cell lines representing all breast cancer subtypes, expression of candidate factors was assessed in response to agonist DHT and antagonist enzalutamide. Gene set enrichment analysis (GSEA) was performed on publically available gene expression datasets from breast cancer patients to analyze the relationship between genes encoding the secreted factors and other androgen responsive gene sets in each breast cancer subtype. RESULTS: Anti-androgen treatment decreased proliferation in all cell lines tested representing various tumor subtypes. Expression of the secreted factors was regulated by AR activation in the majority of breast cancer cell lines. In GSEA, the candidate genes were positively correlated with an androgen responsive gene set across breast cancer subtypes. CONCLUSION: KLK3, AZGP1 and PIP are AR regulated and reflect tumor AR activity. Further investigations are needed to examine the potential efficacy of these factors as serum biomarkers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13058-021-01478-9. BioMed Central 2021-11-04 2021 /pmc/articles/PMC8567567/ /pubmed/34736512 http://dx.doi.org/10.1186/s13058-021-01478-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Hanamura, Toru Christenson, Jessica L. O’Neill, Kathleen I. Rosas, Emmanuel Spoelstra, Nicole S. Williams, Michelle M. Richer, Jennifer K. Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title | Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title_full | Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title_fullStr | Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title_full_unstemmed | Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title_short | Secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
title_sort | secreted indicators of androgen receptor activity in breast cancer pre-clinical models |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567567/ https://www.ncbi.nlm.nih.gov/pubmed/34736512 http://dx.doi.org/10.1186/s13058-021-01478-9 |
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