Human Molecular Genetics Advance Access published online on October 21, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg347
© 2003 by Oxford University Press
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1 National Cancer Centre, 11 Hospital Drive, Singapore 169610, Republic of Singapore
* To whom correspondence should be addressed. E-mail: cmrtan{at}nccs.com.sg.
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 to 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.
Article
Classifying the Estrogen Receptor Status of Breast Cancers by Expression Profiles Reveals a Poor Prognosis Subpopulation Exhibiting High Expression of the ERBB2 Receptor
2 Department of Pathology, 11 Hospital Drive, Singapore 169610, Republic of Singapore
3 Institute for Infocomm Research, 21 Heng Mui Keng Terrace, Singapore 119613, Republic of Singapore
4 National Cancer Centre, 11 Hospital Drive, Singapore 169610, Republic of Singapore; Defence Medical Research Institute, 11 Hospital Drive, Singapore 169610, Republic of Singapore
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