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Cell cycle-coupled expansion of AR activity promotes cancer progression.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

McNair, C 
Urbanucci, A 
Comstock, CES 
Augello, MA 
Goodwin, JF 

Abstract

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

Description

Keywords

Androgens, Base Sequence, Binding Sites, Cell Cycle, Cluster Analysis, Computational Biology, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Models, Biological, Neoplasms, Nucleotide Motifs, Phenotype, Prognosis, Protein Binding, Receptors, Androgen

Journal Title

Oncogene

Conference Name

Journal ISSN

0950-9232
1476-5594

Volume Title

36

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Cancer Research UK (C14303/A17197)
Cancer Research UK (20411)