Human Molecular Genetics Advance Access originally published online on October 21, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 24 3245-3258
DOI: 10.1093/hmg/ddg347
© 2003 Oxford University Press
Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor
1National Cancer Centre, 2Department of Pathology and 3Defence Medical Research Institute, 11 Hospital Drive, Singapore 169610, Republic of Singapore and 4Institute for Infocomm Research, 21 Heng Mui Keng Terrace, Singapore 119613, Republic of Singapore
Received July 4, 2003; Accepted October 9, 2003
Recent work using expression profiling to computationally predict the estrogen receptor (ER) status of breast tumors has revealed that certain tumors are characterized by a high prediction uncertainty (‘low-confidence’). We analyzed these ‘low-confidence’ tumors and determined that their ‘uncertain’ prediction status arises as a result of widespread perturbations in multiple genes whose expression is important for ER subtype discrimination. Patients with ‘low-confidence’ ER+ tumors exhibited a significantly worse overall survival (P=0.03) and shorter time to distant metastasis (P=0.004) compared with their ‘high-confidence’ ER+ counterparts, indicating that the ‘high-’ and ‘low-confidence’ binary distinction is clinically meaningful. We then discovered that elevated expression of the ERBB2 receptor is significantly correlated with a breast tumor exhibiting a ‘low-confidence’ prediction, and this association was subsequently validated across multiple independently derived breast cancer expression datasets employing a variety of different array technologies and patient populations. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ER, a large proportion of the perturbed genes in the ‘low-confidence’/ERBB2+ samples are not known to be estrogen responsive, and a recently described bioinformatic algorithm (DEREF) was used to demonstrate the absence of potential estrogen-response elements (EREs) in their promoters. We propose that a significant portion of ERBB2's effects on ER+ breast tumors may involve ER-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the ‘low-confidence’ breast tumor subtype.
* To whom correspondence should be addressed. Tel: +65 64368345; Fax: +65 62265694; Email: cmrtan{at}nccs.com.sg
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Raulic, Y. Ramos-Valdes, and G. E DiMattia Stanniocalcin 2 expression is regulated by hormone signalling and negatively affects breast cancer cell viability in vitro J. Endocrinol., June 1, 2008; 197(3): 517 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K.T. Tan, L. K. Tan, K. Yu, P. H. Tan, M. Lee, L. H. Sii, C. Y. Wong, G. H. Ho, A. W.Y. Yeo, P. K.H. Chow, et al. Clinical Validation of a Customized Multiple Signature Microarray for Breast Cancer Clin. Cancer Res., January 15, 2008; 14(2): 461 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Lin, S. Reierstad, C.-C. Huang, and S. E. Bulun Novel Estrogen Receptor-{alpha} Binding Sites and Estradiol Target Genes Identified by Chromatin Immunoprecipitation Cloning in Breast Cancer Cancer Res., May 15, 2007; 67(10): 5017 - 5024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. E. Harvell, J. K. Richer, D. C. Allred, C. A. Sartorius, and K. B. Horwitz Estradiol Regulates Different Genes in Human Breast Tumor Xenografts Compared with the Identical Cells in Culture Endocrinology, February 1, 2006; 147(2): 700 - 713. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Siddique, C. Balram, L. Fiszer-Maliszewska, A. Aggarwal, A. Tan, P. Tan, K. C. Soo, and K. Sabapathy Evidence for Selective Expression of the p53 Codon 72 Polymorphs: Implications in Cancer Development Cancer Epidemiol. Biomarkers Prev., September 1, 2005; 14(9): 2245 - 2252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. X. Jin, Y.-W. Leu, S. Liyanarachchi, H. Sun, M. Fan, K. P. Nephew, T. H.-M. Huang, and R. V. Davuluri Identifying estrogen receptor {alpha} target genes using integrated computational genomics and chromatin immunoprecipitation microarray Nucleic Acids Res., December 17, 2004; 32(22): 6627 - 6635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Modlich, H.-B. Prisack, M. Munnes, W. Audretsch, and H. Bojar Immediate Gene Expression Changes After the First Course of Neoadjuvant Chemotherapy in Patients with Primary Breast Cancer Disease Clin. Cancer Res., October 1, 2004; 10(19): 6418 - 6431. [Abstract] [Full Text] [PDF]
|
|