Secreted indicators of androgen receptor activity in breast cancer pre-clinical models

Abstract 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...

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Autores principales:	Toru Hanamura, Jessica L. Christenson, Kathleen I. O’Neill, Emmanuel Rosas, Nicole S. Spoelstra, Michelle M. Williams, Jennifer K. Richer
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Breast cancer Androgen signal Androgen receptor Serum factor KLK3 AZGP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0371be8231394e019312e132cfe5dbce
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spelling	oai:doaj.org-article:0371be8231394e019312e132cfe5dbce2021-11-07T12:18:43ZSecreted indicators of androgen receptor activity in breast cancer pre-clinical models10.1186/s13058-021-01478-91465-542Xhttps://doaj.org/article/0371be8231394e019312e132cfe5dbce2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13058-021-01478-9https://doaj.org/toc/1465-542XAbstract 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.Toru HanamuraJessica L. ChristensonKathleen I. O’NeillEmmanuel RosasNicole S. SpoelstraMichelle M. WilliamsJennifer K. RicherBMCarticleBreast cancerAndrogen signalAndrogen receptorSerum factorKLK3AZGP1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENBreast Cancer Research, Vol 23, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Breast cancer Androgen signal Androgen receptor Serum factor KLK3 AZGP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Breast cancer Androgen signal Androgen receptor Serum factor KLK3 AZGP1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Toru Hanamura Jessica L. Christenson Kathleen I. O’Neill Emmanuel Rosas Nicole S. Spoelstra Michelle M. Williams Jennifer K. Richer Secreted indicators of androgen receptor activity in breast cancer pre-clinical models
description	Abstract 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.
format	article
author	Toru Hanamura Jessica L. Christenson Kathleen I. O’Neill Emmanuel Rosas Nicole S. Spoelstra Michelle M. Williams Jennifer K. Richer
author_facet	Toru Hanamura Jessica L. Christenson Kathleen I. O’Neill Emmanuel Rosas Nicole S. Spoelstra Michelle M. Williams Jennifer K. Richer
author_sort	Toru Hanamura
title	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_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_sort	secreted indicators of androgen receptor activity in breast cancer pre-clinical models
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0371be8231394e019312e132cfe5dbce
work_keys_str_mv	AT toruhanamura secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT jessicalchristenson secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT kathleenioneill secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT emmanuelrosas secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT nicolesspoelstra secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT michellemwilliams secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels AT jenniferkricher secretedindicatorsofandrogenreceptoractivityinbreastcancerpreclinicalmodels
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Secreted indicators of androgen receptor activity in breast cancer pre-clinical models

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