The glucose transporter GLUT1 is required for ErbB2-induced mammary tumorigenesis

Abstract

BackgroundAltered tumor cell metabolism is an emerging hallmark of cancer; however, the precise role for glucose in tumor initiation is not known. GLUT1 (SLC2A1) is expressed in breast cancer cells and is likely responsible for avid glucose uptake observed in established tumors. We have shown that GLUT1 was necessary for xenograft tumor formation from primary mammary cells transformed with the polyomavirus middle-T antigen but that it was not necessary for growth after tumors had formed in vivo, suggesting a differential requirement for glucose depending on the stage of tumorigenesis.MethodsTo determine whether GLUT1 is required early during mammary tumorigenesis, we crossed MMTV-NIC mice, which express activated HER2/NEU/ERBB2 and Cre recombinase, to Slc2a1 Flox/Flox (GLUT1Flox/Flox) mice to generate NIC-GLUT1+/+, NIC-GLUT1Flox/+, and NIC-GLUT1Flox/Flox mice. In addition, we evaluated effects of glucose restriction or GLUT1 inhibition on transformation in MCF10A-ERBB2 breast epithelial cells in three-dimensional culture. Finally, we utilized global gene expression profiling data of primary human breast tumors to determine the relationship between SLC2A1 and stage of tumorigenesis.ResultsAll of the NIC-GLUT1+/+ mice developed tumors in less than 200 days. In contrast, only 1 NIC-GLUT1Flox/Flox mouse and 1 NIC-GLUT1Flox/+ mouse developed mammary tumors, even after 18 months. Mammary gland development was not disrupted in NIC mice lacking GLUT1; however, epithelial content of mature glands was reduced compared to NIC-GLUT1Flox/+ mice. In MCF10A-ERBB2 cells, glucose restriction or GLUT1 inhibition blocked transformation induced by activated ERBB2 through reduced cell proliferation. In human breast cancers, SLC2A1 was higher in ductal carcinoma in situ compared to the normal breast, but lower in invasive versus in situ lesions, suggesting the requirement for GLUT1 decreases as tumors progress.ConclusionsThis study demonstrates a strict requirement for GLUT1 in the early stages of mammary tumorigenesis in vitro and in vivo. While metabolic adaptation has emerged as a hallmark of cancer, our data indicate that early tumor cells rely heavily on glucose and highlight the potential for glucose restriction as a breast cancer preventive strategy.

Targeting Glucose Transporters for Breast Cancer Therapy: The Effect of Natural and Synthetic Compounds

“…GLUT1 is a transporter ubiquitously expressed in most mammalian tissues (abundantly in brain and erythrocytes), being responsible for basal glucose cellular uptake in the majority of tissues [16,17]; it is also the predominant isoform present in human and bovine mammary glands [24,25]. Glucose uptake mediated by GLUT1 appears to be especially critical in the early stages of breast cancer development, affecting cell transformation and tumor formation [26,27]. Indeed, GLUT1 overexpression, which occurs early during the transformation process, induces a change in breast epithelial cell metabolism that precedes morphological changes in breast cancer, and thus may be a fundamental part of the neoplastic process [18].…”

“…Indeed, GLUT1 overexpression, which occurs early during the transformation process, induces a change in breast epithelial cell metabolism that precedes morphological changes in breast cancer, and thus may be a fundamental part of the neoplastic process [18]. Interestingly, the loss of even a single GLUT1 allele is sufficient to impose a strong break in breast tumor development in a mouse model [26]. A strong correlation between GLUT1 gene expression and breast cancers of higher grade and proliferative index and lower degree of differentiation [28] and higher malignant potential, invasiveness, and consequently poorer prognosis [29] exists.…”

“…Of interest, STF31 (30 µM) potentiated the antiproliferative effect of metformin (3 mM) in MDA-MB-231 cells [57]. Although the effect on glucose uptake was not studied, GLUT1 inhibition (with WZB117) blocked transformation of MCF10A-ERBB2 cells (a breast epithelial cell line used as a model to study the early events leading to transformation) induced by activated ERBB2 through reduced cell proliferation [26] (Table 1).…”

PRL-3 improves colorectal cancer cell proliferation and invasion through IL-8 mediated glycolysis metabolism

“…PRL-3 improves growth and invasion via glycolysis in colorectal cancer cells. Lactate and glycolysis-associated enzymes and molecules have been found to play important roles in improving cancer cell metastasis (15)(16)(17)(18)(19). To identify the role of PRL-3 induced glycolysis through IL-8 on colorectal cancer cell growth and invasion, we inhibited lactate by pretreating colorectal cancer cells with oxamic acid, or we inhibited Glut1, HK2, PKM2 or LDHA expression by siRNA, or we inhibited IL-8 by pretreating anti-IL-8 antibody.…”

Targeted Delivery of siRNA with pH-Responsive Hybrid Gold Nanostars for Cancer Treatment

“…2-Amino-2-deoxy- d -glucose (DG) is a kind of glucose analogue which is capable of selective combination with glucose transporter 1 (GLUT1). GLUT1 is a vital prognostic indicator of tumorigenesis [ 30 , 31 , 32 ]. When GLUT1 is present on cell membranes, it can recognize and transport DG into cells, thus DG has the effect of targeting tumor cells [ 33 , 34 , 35 ].…”