Breast cancer prognosis predicted by nuclear receptor-coregulator networks.
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.
Westmead Millennium Institute, Sydney Medical School - Westmead, University of Sydney, NSW, Australia.
Tram B
TB
Doan
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia.
Natalie A
NA
Eriksson
Westmead Millennium Institute, Sydney Medical School - Westmead, University of Sydney, NSW, Australia.
Dinny
D
Graham
Prince Henry's Institute of Medical Research, Clayton, VIC, Australia.
John W
JW
Funder
Prince Henry's Institute of Medical Research, Clayton, VIC, Australia.
Evan R
ER
Simpson
Sydney Medical School, University of Sydney, Westmead, NSW, Australia.
Elizabeth S
ES
Kuczek
Prince Henry's Institute of Medical Research, Clayton, VIC, Australia.
Colin
C
Clyne
Laboratory for Cancer Medicine, Centre for Medical Research, Western Australian Institute for Medical Research and School of Medicine and Pharmacology, the University of Western Australia, Perth, WA, Australia.
Peter J
PJ
Leedman
Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, Hanson Institute, University of Adelaide, Adelaide, SA, Australia.
Wayne D
WD
Tilley
Prince Henry's Institute of Medical Research, Clayton, VIC, Australia.
Peter J
PJ
Fuller
Institute for Molecular Bioscience, University of Queensland, St. Lucia, QLD, Australia. Electronic address: G.Muscat@uq.edu.au.
George E O
GE
Muscat
Westmead Millennium Institute, Sydney Medical School - Westmead, University of Sydney, NSW, Australia. Electronic address: christine.clarke@sydney.edu.au.
Christine L
CL
Clarke
D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D059467:Transcriptome
D018160:Receptors, Cytoplasmic and Nuclear
Breast; Gene signature; Nuclear receptors; Prognosis; Transcriptome