title: Expression of endoplasmic reticulum stress proteins is a candidate marker of brain metastasis in both ErbB-2+ and ErbB-2- primary breast tumors.
abstract: 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, FN14, 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.
authors.affiliation: Biological Clues of the Invasive and Metastatic Phenotype Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Sanz-Pamplona
authors.forename: Ramón
authors.initials: R
authors.lastname: Aragüés
authors.forename: Keltouma
authors.initials: K
authors.lastname: Driouch
authors.forename: Berta
authors.initials: B
authors.lastname: Martín
authors.forename: Baldo
authors.initials: B
authors.lastname: Oliva
authors.forename: Miguel
authors.initials: M
authors.lastname: Gil
authors.forename: Susana
authors.initials: S
authors.lastname: Boluda
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Fernández
authors.forename: Antonio
authors.initials: A
authors.lastname: Martínez
authors.forename: Víctor
authors.initials: V
authors.lastname: Moreno
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Acebes
authors.forename: Rosette
authors.initials: R
authors.lastname: Lidereau
authors.forename: Fabien
authors.initials: F
authors.lastname: Reyal
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Van de Vijver
authors.forename: Angels
authors.initials: A
authors.lastname: Sierra
mesh_terms: D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism*; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007265:Inhibins / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D000074050:TWEAK Receptor
chemical_list: D014408:Biomarkers, Tumor; D007265:Inhibins; D008562:Membrane Glycoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613297:TNFRSF12A protein, human; C053387:endoplasmin; C508053:ERBB2 protein, human