Abstract 892: Alterations of vitamin B1 homeostasis following oxidative stress in breast cancer and impact of supplementation on cellular redox homeostasis

Abstract

Abstract Vitamin B1, or thiamine, has been demonstrated to enhance the development and growth of breast tumors in vivo. In addition, alterations in the expression of critical thiamine homeostasis genes have been extensively described in pre-clinical models of breast cancer as well as in clinical breast tumor tissue. Despite the effort that has been placed on delineating alterations to thiamine homeostasis that occur during breast cancer, there remains little evidence demonstrating a molecular advantage for supplemental thiamine in breast cancer cells. Our previous work in colorectal cancer suggests that the proliferative benefits of thiamine may be related to the maintenance of oxidative stress. This appears to be facilitated through the adaptive regulation of the thiamine activating enzyme thiamine pyrophosphokinase-1 (TPK1) for thiamine pyrophosphate production. Here, using MCF7 cells as a model of breast cancer, we also identified a relationship between thiamine homeostasis and oxidative stress. Similar to previous findings in colorectal cancer, Western blot analysis revealed that TPK1 expression was up-regulated in response to enhanced levels of ROS induced by hypoxia and chemotherapeutic treatment. TPK1 knockdown mediated by shRNA reduced the proliferation of MCF7 cells, while the presence of supplemental thiamine promoted proliferation as determined by cell counting. The effect of supplemental thiamine on MCF7 proliferation corresponded with a direct impact to the antioxidant status of tumor cells measured by reduced nuclear accumulation of the transcription factor nuclear factor- erythroid 2-related factor 2 by Western blot analysis. Molecular probes detecting intracellular ROS revealed that supplemental thiamine did not reduce the basal level of ROS in MCF7 cells. However, enhanced thiamine reduced intracellular superoxide levels following stimulation with the electron transport chain inhibitor Antimycin A. These findings support that during supplemental thiamine conditions thiamine homeostasis may be exploited in breast cancer for a redox advantage contributing to tumor progression. Citation Format: Hunter C. Jonus, Ashley E. Ray, Jason A. Zastre. Alterations of vitamin B1 homeostasis following oxidative stress in breast cancer and impact of supplementation on cellular redox homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 892.