Breast cancer prognosis predicted by nuclear receptor-coregulator networks

Doan, Tram B., Eriksson, Natalie A., Graham, Dinny, Funder, John W., Simpson, Evan R., Kuczek, Elizabeth S., Clyne, Colin, Leedman, Peter J., Tilley, Wayne D., Fuller, Peter J., Muscat, George E. O. and Clarke, Christine L. (2014) Breast cancer prognosis predicted by nuclear receptor-coregulator networks. Moelcular Oncology, 8 5: 998-1013. doi:10.1016/j.molonc.2014.03.017

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Author Doan, Tram B.
Eriksson, Natalie A.
Graham, Dinny
Funder, John W.
Simpson, Evan R.
Kuczek, Elizabeth S.
Clyne, Colin
Leedman, Peter J.
Tilley, Wayne D.
Fuller, Peter J.
Muscat, George E. O.
Clarke, Christine L.
Title Breast cancer prognosis predicted by nuclear receptor-coregulator networks
Journal name Moelcular Oncology   Check publisher's open access policy
ISSN 1574-7891
Publication date 2014-01-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.molonc.2014.03.017
Open Access Status File (Author Post-print)
Volume 8
Issue 5
Start page 998
End page 1013
Total pages 16
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Language eng
Subject 1313 Molecular Medicine
1311 Genetics
1306 Cancer Research
Abstract Although molecular signatures based on transcript expression in breast cancer samples have provided new insights into breast cancer classification and prognosis, there are acknowledged limitations in current signatures. To provide rational, pathway-based signatures of disrupted physiology in cancer tissues that may be relevant to prognosis, this study has directly quantitated changed gene expression, between normal breast and cancer tissue, as a basis for signature development. The nuclear receptor (NR) family of transcription factors, and their coregulators, are fundamental regulators of every aspect of metazoan life, and were rigorously quantified in normal breast tissues and ERα positive and ERα negative breast cancers. Coregulator expression was highly correlated with that of selected NR in normal breast, particularly from postmenopausal women. These associations were markedly decreased in breast cancer, and the expression of the majority of coregulators was down-regulated in cancer tissues compared with normal. While in cancer the loss of NR-coregulator associations observed in normal breast was common, a small number of NR (Rev-ERBβ, GR, NOR1, LRH-1 and PGR) acquired new associations with coregulators in cancer tissues. Elevated expression of these NR in cancers was associated with poorer outcome in large clinical cohorts, as well as suggesting the activation of ERα -related, but ERα-independent, pathways in ERα negative cancers. In addition, the combined expression of small numbers of NR and coregulators in breast cancer was identified as a signature predicting outcome in ERα negative breast cancer patients, not linked to proliferation and with predictive power superior to existing signatures containing many more genes. These findings highlight the power of predictive signatures derived from the quantitative determination of altered gene expression between normal breast and breast cancers. Taken together, the findings of this study identify networks of NR-coregulator associations active in normal breast but disrupted in breast cancer, and moreover provide evidence that signatures based on NR networks disrupted in cancer can provide important prognostic information in breast cancer patients.
Keyword Breast
Nuclear receptors
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID CG-08-03
Institutional Status UQ
Additional Notes Published online ahead of print 4 April 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 8 times in Thomson Reuters Web of Science Article | Citations
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Created: Thu, 22 May 2014, 21:15:18 EST by Susan Allen on behalf of Institute for Molecular Bioscience