TP53 gain-of-function mutations increase glucose uptake via GLUT1 membrane translocation in patients with breast cancer

Description

Glucose metabolism in malignancies plays an important role in tumor growth and progression. Investigators have paid attention to this glucose-addiction in cancer cells and based on the biologic characteristics of cancer glucose metabolism, 18-fluorodeoxyglucose-positron emission tomography (18f-FDG-PET) was invented. The standardized uptake value (SUV), which represents glucose uptake as an objective parameter, has been recognized as a prognostic factor for patients with breast cancer. In addition, it has been shown that elevated SUV is associated with high histologic grade and Ki67 expression. Therefore, the identification of key molecules associated with activated glycolysis in breast cancer might broaden our understanding of breast cancer biology and potentially lead to new therapeutic targets. In our study, we utilized microarray technology to measure gene expression levels based on SUV and observed a significant association between elevated SUV and TP53. Further, we found that TP53 mutations in breast cancer patients were positively linked with increased GLUT1 membrane expression. To validate these findings, in vitro experiments with normal mammary epithelial cells were performed. We generated MCF10A cell lines with R175H, R273H, and R248W variants of mutant-p53 and discovered that glucose uptake increased by 1.5-1.8 fold compared to wild-type or p53-knockdown MCF-10A cells. In mutant p53-MCF-10A cells, GLUT1 translocated to the membrane while it remained diffusely expressed in the cytoplasm of wild-type and p53-knockdown cells. Our study confirms that TP53 mutations have an adverse impact on survival and lead to elevated glucose uptake by promoting GLUT1 membrane translocation.

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