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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2009

01-03-2009 | Preclinical Study

Molecular profiles of progesterone receptor loss in human breast tumors

Authors: Chad J. Creighton, C. Kent Osborne, Marc J. van de Vijver, John A. Foekens, Jan G. Klijn, Hugo M. Horlings, Dimitry Nuyten, Yixin Wang, Yi Zhang, Gary C. Chamness, Susan G. Hilsenbeck, Adrian V. Lee, Rachel Schiff

Published in: Breast Cancer Research and Treatment | Issue 2/2009

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Abstract

Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR− compared to ER+/PR+ tumors. Methods To better understand the underlying biology of ER+/PR− tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR−, and ER−/PR−). Results We identified an expression “signature” of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER−/PR− and ER+/PR− tumors. We similarly identified a gene signature specific to ER−/PR− tumors. ER+/PR− tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER−/PR− signature, and tumors not associating with ER+/PR+ or ER−/PR− tumors (which we considered “true” ER+/PR−). In analyses of both tamoxifen-treated and untreated patients, ER+/PR− breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR− tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER−PR− tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR− and ER−/PR− compared to ER+/PR+ tumors. Conclusion ER+/PR− tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.
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Metadata
Title
Molecular profiles of progesterone receptor loss in human breast tumors
Authors
Chad J. Creighton
C. Kent Osborne
Marc J. van de Vijver
John A. Foekens
Jan G. Klijn
Hugo M. Horlings
Dimitry Nuyten
Yixin Wang
Yi Zhang
Gary C. Chamness
Susan G. Hilsenbeck
Adrian V. Lee
Rachel Schiff
Publication date
01-03-2009
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2009
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-008-0017-2

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