Abstract
Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.
Highlights
Glioblastoma (GBM) is the most aggressive primary brain cancer in adults [1], and about 13,000Glioblastoma (GBM) is the most aggressive primary brain cancer in adults [1], and about cases arise annually in the USA [2]
To determine whether ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed in GBM, we measured total ERBB4 expression in GBM samples derived from patients diagnosed with World Health Organization WHO grade III or IV primary glioma, neoplastic normal brain (NNB) and Ref Brain
Total ERBB4 mRNA levels were significantly lower in GBM
Summary
Glioblastoma (GBM) is the most aggressive primary brain cancer in adults [1], and about cases arise annually in the USA [2]. GBM tumors are diffuse [3] and highly invasive, therapeutic resistance [4,5], resulting in high morbidity and mortality (median survival,
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