The
hexosamine biosynthetic pathway (HBP) metabolically regulates dynamic cellular events by linking nutrient availability to numerous signaling networks. Significant alterations in the HBP are often associated with
cancer pathogenesis. In this study, we investigated the molecular events underlying
cancer pathogenesis associated with enhanced HBP flux. Multidimensional analysis of microarray datasets demonstrated up-regulation of genes encoding HBP
enzymes in clinical breast
cancers and revealed that co-expression of
hyaluronan synthase 2 (HAS2) and
glutamine:fructose-6-phosphate amidotransferase (GFAT), a rate-limiting
enzyme of the HBP, was strongly correlated with a poor prognosis in advanced
cancer patients. Consistently with the clinical data, comparative analyses of distinct
breast cancer mouse models demonstrated enhancement of the HBP gene expression in primary
carcinoma cells, with elevation of Has2 expression and
hyaluronan production in aggressive
breast cancer cells. The silencing of GFAT reduced CD44high/CD24low cancer stem cell (CSC)-like subpopulations,
aldehyde dehydrogenase-positive cell populations, and mammosphere size, which were further diminished by gene targeting of Has2. Has2 gene disruption reduced the in vivo growth of aggressive
cancer cells and attenuated pro-tumorigenic Akt/GSK3β/β-
catenin signaling and
cisplatin resistance. Overall
protein O-GlcNAcylation was also elevated in association with HBP enhancement in aggressive
cancer cells, and the modification exhibited overlapping but distinct roles from the
hyaluronan signal in the regulation of CSC-like features. The current data therefore demonstrate that enhanced
hexosamine metabolism drives pro-tumorigenic signaling pathways involving
hyaluronan and O-GlcNAcylation in aggressive
breast cancer.