Research article
Inhibitory effects of estrogen receptor beta on specific hormone-responsive gene expression and association with disease outcome in primary breast cancer
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* Corresponding author: Edison T Liu liue@gis.a-star.edu.sg
1 Genome Institute of Singapore, 60 Biopolis Street, #02-01, Singapore 138672, Republic of Singapore
2 Department of Microbiology and Molecular Biology, Brigham Young University, 753 WIDB, Provo, UT 84602, USA
3 Center for Biotechnology, Karolinska Institute, Hälsovägen 7-9, 141 57 Huddinge, Novum, Sweden
4 Radiumhemmet, Karolinska Institute and University Hospital, S-171 76 Stockholm, Sweden
5 Department of Biosciences and Nutrition, Karolinska Institute, Hälsovägen 7-9, 141 57 Huddinge, Novum, Sweden
Breast Cancer Research 2007, 9:R25 doi:10.1186/bcr1667
See related editorial by Shupnik, http://breast-cancer-research.com/content/9/3/107
Published: 10 April 2007Abstract
Introduction
The impact of interactions between the two estrogen receptor (ER) subtypes, ERα and ERβ, on gene expression in breast cancer biology is not clear. The goal of this study was to examine transcriptomic alterations in cancer cells co-expressing both receptors and the association of gene expression signatures with disease outcome.
Methods
Transcriptional effects of ERβ overexpression were determined in a stably transfected cell line derived from ERα-positive T-47D cells. Microarray analysis was carried out to identify differential gene expression in the cell line, and expression of key genes was validated by quantitative polymerase chain reaction. Microarray and clinical data from patient samples were then assessed to determine the in vivo relevance of the expression profiles observed in the cell line.
Results
A subset of 14 DNA replication and cell cycle-related genes was found to be specifically downregulated by ERβ. Expression profiles of four genes, CDC2, CDC6, CKS2, and DNA2L, were significantly inversely correlated with ERβ transcript levels in patient samples, consistent with in vitro observations. Kaplan-Meier analysis revealed better disease outcome for the patient group with an expression signature linked to higher ERβ expression as compared to the lower ERβ-expressing group for both disease-free survival (p = 0.00165) and disease-specific survival (p = 0.0268). These findings were further validated in an independent cohort.
Conclusion
Our findings revealed a transcriptionally regulated mechanism for the previously described growth inhibitory effects of ERβ in ERα-positive breast tumor cells and provide evidence for a functional and beneficial impact of ERβ in primary breast tumors.