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

Abstract

// Antonio Martínez-Aranda 1, 2 , Vanessa Hernández 1 , Emre Guney 3 , Laia Muixí 1 , Ruben Foj 1, 2 , Núria Baixeras 4 , Daniel Cuadras 5 , Víctor Moreno 5 , Ander Urruticoechea 6 , Miguel Gil 7 , Baldo Oliva 3 , Ferran Moreno 8 , Eva González-Suarez 9 , Noemí Vidal 4 , Xavier Andreu 10 , Miquel A. Seguí 11 , Rosa Ballester 12 , Eva Castella 13 , Angels Sierra 1, 14 1 Biological Clues of the Invasive and Metastatic Phenotype Group, Molecular Oncology Department, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L’Hospitalet de Llobregat, Barcelona, Spain 2 Universitat Autònoma de Barcelona (UAB), Biochemistry and Molecular Biology Department, Faculty of Biosciences, Campus Bellaterra, Edifici C, Cerdanyola del Vallés, 08193 Barcelona, Spain 3 Structural Bioinformatics Laboratory, Experimental Sciences Department, Universitat Pompeu Fabra-IMIM, Barcelona Research Park of Biomedicine, 08003 Barcelona, Spain 4 Servei d’Anatomia Patològica, Hospital Universitari de Bellvitge, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 5 Biomarkers and Susceptibility Unit, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 6 Breast Cancer Unit and Neuroncology Unit, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 7 Oncology Service, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 8 Radiation Oncology Service, Institut Català d’Oncologia - IDIBELL, Hospital Duran i Reynals, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 9 Transformation and Metastasis Group, Cancer Epigenetics and Biology Department, IDIBELL, 08907 L’Hospitalet de Llobregat, Barcelona, Spain 10 Pathology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain 11 Oncology Service, Corporació Sanitaria Parc Taulí, 08208 Sabadell, Spain 12 Radiation Oncology Service, Institut Català d’Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain 13 Pathology Service, Institut Català d’Oncologia, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain 14 Molecular and Translational Oncology Laboratory, Biomedical Research Center CELLEX-CRBC Institut d’Investigacions Biomèdiques August Pi i Sunyer-IDIBAPS 08036 Barcelona, Spain Correspondence to: Angels Sierra, e-mail: asierrajim@gmail.com , masierra@clinic.ub.es Keywords: biomarkers, brain metastasis, breast cancer, FN14, GRP94 Received: April 17, 2015      Accepted: October 09, 2015      Published: October 19, 2015 ABSTRACT 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.