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.

MiR-410 Acts as a Tumor Suppressor in Estrogen Receptor-Positive Breast Cancer Cells by Directly Targeting ERLIN2 via the ERS Pathway

“…Andrographolide induces apoptosis of colon cancer cells via the upregulation of ERS proteins GRP78, CHOP as well as the decreased BAX/Bcl-2 ration [33]. ERS pathway is also reported to participate in the malignancy of diverse cancers, such as the metastasis of breast cancer [34,35], the poor progression of gastric carcinoma [36] as well as anti-cancer drug resistance of lung cancer cells and ovarian carcinoma cells [37]. Moreover, another study also demonstrates Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry that icariin exerts anti-tumor activity by upregulating the expression of ERS -related molecules (GRP78, CHOP, p-PERK and p-eIF2a), resulting in the inhibition of cell migration, adhesion and increase in apoptosis [38].…”

Endoplasmic Reticulum-resident Heat Shock Protein 90 (HSP90) Isoform Glucose-regulated Protein 94 (GRP94) Regulates Cell Polarity and Cancer Cell Migration by Affecting Intracellular Transport

“…GRP94 Promotes Tumorigenesis-Previous reports have indicated that GRP94 is a pro-oncogenic chaperone (13) that promotes cell adhesion and causes tumorigenesis and metastasis in various organs (56,57). A three-dimensional in vitro tumor formation assay was used to investigate whether the defects in GRP94 knockdown cells would translate into defects in tumor formation and metastasis.…”

Fn14 receptor promotes invasive potential and metastatic capacity of non-small lung adenocarcinoma cells through the up-regulation of integrin α6

“…On the other hand, low Fn14 expression correlated with lymph node-negative disease and well differentiated tumors, what is indicative of good prognosis [15]. Another group reported that in breast adenocarcinomas, certain proteins including Fn14 associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastases [35]. Recently, it was suggested that Fn14 protein is a valuable marker of breast carcinoma progression and might be a good prognostic marker for breast carcinoma patients [23].…”