Tumor and Stem Cell Biology Oncogene Pathway Activation in Mammary Tumors Dictates FDG-PET Uptake

Increased glucose utilization is a hallmark of human cancer that is used to image tumors clinically. In this widely used application, glucose uptake by tumors is monitored by positron emission tomography of the labeled glucose analogue 2[F]fluoro-2-deoxy-D-glucose (FDG). Despite its widespread clinical use, the cellular and molecular mechanisms that determine FDG uptake—and that underlie the heterogeneity observed across cancers—remain poorly understood. In this study, we compared FDG uptake in mammary tumors driven by the Akt1, c-MYC,HER2/neu,Wnt1, orH-Ras oncogenes in genetically engineeredmice, correlating it to tumor growth, cell proliferation, and expression levels of gene involved in key steps of glycolytic metabolism.We found that FDG uptake by tumors was dictated principally by the driver oncogene and was not independently associated with tumor growth or cellular proliferation. Oncogene downregulation resulted in a rapid decrease in FDG uptake, preceding effects on tumor regression, irrespective of the baseline level of uptake. FDG uptake correlated positively with expression of hexokinase-2 (HK2) and hypoxia-inducible factor-1a (HIF1a) and associated negatively with PFK-2b expression and p-AMPK. The correlation betweenHK2 and FDG uptake was independent of all variables tested, including the initiating oncogene, suggesting that HK2 is an independent predictor of FDG uptake. In contrast, expression of Glut1 was correlated with FDG uptake only in tumors driven by Akt or HER2/ neu. Together, these results demonstrate that the oncogenic pathway activated within a tumor is a primary determinant of its FDG uptake, mediated by key glycolytic enzymes, and provide a framework to interpret effects on this key parameter in clinical imaging. Cancer Res; 74(24); 1–16. 2014 AACR.