Abstract A47: Membrane translocation of GLUT1 induced by TP53 mutation is positively correlated with increased glucose uptake in patients with breast cancer

Abstract

Abstract Background: High rate of glycolysis exhibited by cancer cells plays a crucial role in carcinogenesis and tumor progression. To uncover candidate contributing to increasing glucose uptake in breast cancer, we interrogated clinical transcriptome data set from 66 patients undergoing preoperative 18F-fluorodeoxy glucose positron emission tomography (FDG-PET). Also, we validated the candidate in other clinical data and confirm its role in glucose uptake through cell line works. Methods: Clustered analysis by standardized uptake value (SUV) from FDG-PET and gene network analysis suggested that repression of p53 might be a key molecule associated with elevated SUV level. To validate p53 as a major determinant in an elevated glucose uptake, we used second cohort consisted of women with p53 gene sequencing analysis and FDG-PET. Mutational analysis of exons 5-9 of the p53 gene was carried out using polymerase chain reaction-denaturing high performance liquid chromatography. Of these women, to reduce bias and clearly estimate the influence of p53 mutation on SUV and survival, we identified 114 women by propensity-score matching method. Next, among the molecules associated glucose uptake, we compared the expression of GLUT1 using tissue-microarray (TMA). The TMA was constructed using achievable 73 tumors from second cohort with case-matching by P53 mutation status. Then, we validated the role of P53 in glucose uptake by mammary cell using the experiments with MCF-10A cell line. To compare the degree of glucose uptake between P53-mutated and P53-intact cells, we measured gamma activities of these cell lines after treated with 18F-FDG media. Simultaneously, different amount of glucose uptake is visualized using the PET camera. Results: In case-matched cohort by P53 status, the mean SUV of p53-mutational group was significantly higher than that of wild-type p53-group (7.49 vs. 5.44, P=0.013). Compared with the group with intact p53, recurrence-free survival (RFS) was significantly reduced in the group with p53 mutation (P =0.017). In multivariate analysis, p53 mutational status carried prognostic significance (hazard ratio 3.73, 95% CI 1.15-12.07) independent of tumor size, nodal status, and estrogen receptor status. In immunohistochemical stain with GLUT1 using the TMA, we found that the expression of membraneous GLUT1 was significantly higher in P53-mutated tumors than in P53-intact tumor (P=0.022), in support of previous finding showing that P53 mutation promotes GLUT1 translocation to cell membrane. In experiments with MCF10A cell lines, we found that gamma activities and signal intensity by the absorption of18F-glucose were much higher in P53-mutated cell than in P53-intact cell. These experiments showed that the amount of glucose uptake in mammary cell increases followed by P53 mutation, supporting our clinical findings. Conclusion: We showed that TP53 mutation promotes GLUT1 translocation to membrane, which consequently induces glucose influx in patients with breast cancer. In terms of glucose metabolism, P53 mutation caused the increase of glucose uptake within tumor and adversely affect survival in breast cancer. Citation Format: Sung Gwe Ahn, Hak Woo Lee, Airi Han, Jeong Joon. Membrane translocation of GLUT1 induced by TP53 mutation is positively correlated with increased glucose uptake in patients with breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A47.