FN14 and GRP94 expression are prognostic/predictive biomarkers of brain metastasis outcome that open up new therapeutic strategies

• Published in: Oncotarget Vol. 6; no. 42; pp. 44254 - 44273
• Main Authors: Martínez-Aranda, Antonio, Hernández, Vanessa, Guney, Emre, Muixí, Laia, Foj, Ruben, Baixeras, Núria, Cuadras, Daniel, Moreno, Víctor, Urruticoechea, Ander, Gil, Miguel, Oliva, Baldo, Moreno, Ferran, González-Suarez, Eva, Vidal, Noemí, Andreu, Xavier, Seguí, Miquel A, Ballester, Rosa, Castella, Eva, Sierra, Angels
• Format: Journal Article
• Language: English
• Published: United States Impact Journals 29-12-2015; Impact Journals LLC
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors - therapeutic use; Animals; Area Under Curve; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Biochemical markers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - secondary; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - drug therapy; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - secondary; Cell Line, Tumor; Cytokine TWEAK; Càncer de mama; Female; Humans; Immunohistochemistry; Likelihood Functions; Marcadors bioquímics; Melanoma; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Metastasis; Metàstasi; Mice, Nude; Middle Aged; Precision Medicine; Predictive Value of Tests; Prognosis; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Research Paper; Risk Assessment; Risk Factors; ROC Curve; Spain; Thalidomide - therapeutic use; Tissue Array Analysis; Tumor Microenvironment; Tumor Necrosis Factors - metabolism; TWEAK Receptor; Xenograft Model Antitumor Assays; Young Adult; breast cancer; brain metastasis; FN14; biomarkers; GRP94
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5471

Brain metastasis is a devastating problem in patients with breast, lung and melanoma tumors. GRP94 and FN14 are predictive biomarkers over-expressed in primary breast carcinomas that metastasized in brain. To further validate these brain metastasis biomarkers, we performed a multicenter study including 318 patients with breast carcinomas. Among these patients, there were 138 patients with metastasis, of whom 84 had brain metastasis. The likelihood of developing brain metastasis increased by 5.24-fold (95%CI 2.83-9.71) and 2.55- (95%CI 1.52-4.3) in the presence of FN14 and GRP94, respectively. Moreover, FN14 was more sensitive than ErbB2 (38.27 vs. 24.68) with similar specificity (89.43 vs. 89.55) to predict brain metastasis and had identical prognostic value than triple negative patients (p < 0.0001). Furthermore, we used GRP94 and FN14 pathways and GUILD, a network-based disease-gene prioritization program, to pinpoint the genes likely to be therapeutic targets, which resulted in FN14 as the main modulator and thalidomide as the best scored drug. The treatment of mice with brain metastasis improves survival decreasing reactive astrocytes and angiogenesis, and down-regulate FN14 and its ligand TWEAK. In conclusion our results indicate that FN14 and GRP94 are prediction/prognosis markers which open up new possibilities for preventing/treating brain metastasis.