Classifying the estrogen receptor status of breast cancers by expression profiles reveals a poor prognosis subpopulation exhibiting high expression of the ERBB2 receptor

Hum Mol Genet. 2003 Dec 15;12(24):3245-58. doi: 10.1093/hmg/ddg347. Epub 2003 Oct 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Neoplasms, Hormone-Dependent / diagnosis*
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Statistics as Topic
  • Survival Rate
  • Transcriptional Activation


  • Receptor, ErbB-2