Molecular Imaging of GLUT1 and GLUT5 in Breast Cancer: A Multitracer Positron Emission Tomography Imaging Study in Mice

Abstract

Use of [¹⁸F]FDG-positron emission tomography (PET) in clinical breast cancer (BC) imaging is limited mainly by insufficient expression levels of facilitative glucose transporter (GLUT)1 in up to 50% of all patients. Fructose-specific facilitative hexose transporter GLUT5 represents an alternative biomarker for PET imaging of hexose metabolism in BC. The goal of the present study was to compare the uptake characteristics of selected hexose-based PET radiotracers in murine BC model EMT6. Uptake of 1-deoxy-1-[¹⁸F]fluoro-d-fructose (1-[¹⁸F]FDF), 6-deoxy-6-[¹⁸F]fluoro-d-fructose (6-[¹⁸F]FDF), 1-deoxy-1-[¹⁸F]fluoro-2,5-anhydro-mannitol (1-[¹⁸F]FDAM), 2-deoxy-2-[¹⁸F]fluoro-d-glucose (2-[¹⁸F]FDG), and 6-deoxy-6-[¹⁸F]fluoro-d-glucose (6-[¹⁸F]FDG) was studied in EMT6 cells, tumors, and muscle and correlated to GLUT1 and GLUT5 expression levels. Fructose-derivative 6-[¹⁸F]FDF revealed greater tumor uptake than did structural analog 1-[¹⁸F]FDF, whereas 1-[¹⁸F]FDAM with locked anomeric configuration showed similar low tumor uptake to that of 1-[¹⁸F]FDF. Glucose-derivative 6-[¹⁸F]FDG reached maximum tumor uptake at 20 minutes, with no further accumulation over time. Uptake of 2-[¹⁸F]FDG was greatest and continuously increasing owing to metabolic trapping through phosphorylation by hexokinase II. In EMT6 tumors, GLUT5 mRNA expression was 20,000-fold lower compared with GLUT1. Whereas the latter was much greater in tumor than in muscle tissue (GLUT1 50:1), the opposite was found for GLUT5 mRNA expression (GLUT5 1:6). GLUT5 protein levels were higher in tumor versus muscle tissue as determined by Western blot and immunohistochemistry. Our data suggest that tumor uptake of fructose metabolism-targeting radiotracers 1-[¹⁸F]FDF, 6-[¹⁸F]FDF, and 1-[¹⁸F]FDAM does not correlate with GLUT5 mRNA levels but is linked to GLUT5 protein levels. In conclusion, our results highlight the importance of detailed biochemical studies on GLUT protein expression levels in combination with PET imaging studies for functional characterization of GLUTs in BC.