Expression of Endoplasmic Reticulum Stress Proteins Is a Candidate Marker of Brain Metastasis in both ErbB-2(+) and ErbB-2(-) Primary Breast Tumors

Rebeca Sanz-Pamplona, Ramon Araguees, Keltouma Driouch, Berta Martin, Baldo Oliva, Miguel Gil, Susana Boluda, Pedro L. Fernandez, Antonio Martinez, Victor Moreno, Juan J. Acebes, Rosette Lidereau, Fabien Reyal, Marc J. Van de Vijver, Angels Sierra*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)


The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, EN 14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis. (Am J Pathol 2011, 179:564-579; DOI: 10.1016/j.ajpath.2011.04.037)

Original languageEnglish
Pages (from-to)564-579
Number of pages16
JournalAm. J. Pathol.
Issue number2
Publication statusPublished - Aug 2011


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