Identification of Androgen Receptor Modulators in a Prostate Cancer Cell Line Microarray Compendium release_tvciwk3yyreyndkgg54htyjhbu

by John P Rooney, Brian Chorley, Nicole Kleinstreuer, J Christopher Corton

Published in Toxicological Sciences by Oxford University Press (OUP).

2018   Volume 166, Issue 1, p146-162

Abstract

High-throughput transcriptomic (HTTr) technologies are increasingly being used to screen environmental chemicals in vitro to identify molecular targets and provide mechanistic context for regulatory testing. Here, we describe the development and validation of a novel gene expression biomarker to identify androgen receptor (AR)-modulating chemicals using a pattern matching method. Androgen receptor biomarker genes were identified by their consistent expression after exposure to 4 AR agonists and 4 AR antagonists and included only those genes that were regulated by AR. The 51 gene biomarker was evaluated as a predictive tool using the fold-change, rank-based Running Fisher algorithm. Using 158 comparisons from cells treated with 95 chemicals, the biomarker gave balanced accuracies for prediction of AR activation or AR suppression of 97% or 98%, respectively. The biomarker correctly classified 16 out of the 17 AR reference antagonists including those that are "weak" and "very weak". Predictions based on microarray profiles from AR-positive LAPC-4 cells treated with 28 chemicals in antagonist mode were compared with those from an AR pathway model which used 11 in vitro HT assays. The balanced accuracy for suppression was 93%. Using our approach, we identified conditions in which AR was modulated in a large collection of microarray profiles from prostate cancer cell lines including (1) constitutively active mutants or knockdown of AR, (2) decreases in availability of androgens by castration or removal from media, and (3) exposure to chemical modulators that work through indirect mechanisms including suppression of AR expression. These results demonstrate that the AR gene expression biomarker could be a useful tool in HTTr to identify AR modulators.
In text/plain format

Archived Files and Locations

application/pdf  1.4 MB
file_u5he3qwt25gwvee45jnm4xb5ym
europepmc.org (repository)
web.archive.org (webarchive)
Read Archived PDF
Preserved and Accessible
Type  article-journal
Stage   published
Date   2018-07-31
Language   en ?
Container Metadata
Not in DOAJ
In Keepers Registry
ISSN-L:  1096-0929
Work Entity
access all versions, variants, and formats of this works (eg, pre-prints)
Catalog Record
Revision: e0cbf667-d0f6-4cc8-b35c-8dc7a27e8e68
API URL: JSON