Abstract 1486: Increased expression and phosphorylation of eukaryotic initiation factor 4E (eIF4E) and 4E-binding protein (4E-BP1) correlates with disease progression and high risk clinical/pathological features in melanoma

Abstract

Abstract Cutaneous melanoma is an increasingly important public health problem, as the incidence of this disease has increased 15-fold during the last four decades, more than any other malignancy. There is a great need for biomarkers that can be used both for both diagnosis and prognosis in melanoma. Identification of such biomarkers may provide insight into the pathogenesis of this disease, and also suggest rational therapeutic approaches. Protein translation has been shown to play a significant role in carcinogenesis in various organ systems. Several pathways upstream of protein translation are deregulated during melanoma development, including the RAS-RAF-MAPK and the PI3K-AKT kinase cascades. It is unknown whether dysregulated translational machinery contributes to the pathogenesis of melanoma. In order to test the hypothesis that dysregulation of protein translation plays a significant role in melanoma, we have performed immunohistochemical analysis to evaluate expression of phospho-4E-BP1 (p4E-BP1), phospho-eIF4E (peIF4E) and total eIF4E in benign nevi (n=49), primary melanomas (n=130), and melanoma metastases (n=47 cases) specimens obtained from the Department of Pathology of The University of Texas M. D. Anderson Cancer Center. A significant positive correlation was observed between the percentage of positively staining cells and staining intensity for p4E-BP1 (p<0.0001) and peIF4E (p<0.0008) with progression from benign nevi to primary tumors, and from primary tumors to metastases. Significantly higher levels of p4E-BP1 (p=0.0085) and total eIF4E (p=0.0173) proteins were observed in samples with vertical growth phase than in samples with radial growth phase only. Higher levels of p4E-BP1 were also observed in samples with ulceration (p=0.0167), which is a well-established marker of poor clinical outcomes in patients with local and regional melanoma. Thus, total and phosphorylated eIF4E and phosphorylated 4E-BP1 correlate with disease progression and high risk clinical and pathological features in melanoma. These findings provide new insight into the molecular pathogenesis of melanoma, and suggest that protein translation machinery may be an important therapeutic target in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1486.