Abstract 5427: Increased glycolysis by 14-3-3ζ-mediated LDHA up-regulation contributes to transformation of early mammary epithelial cells.

The Warburg effect is a distinct cancer hallmark that shifts the metabolic pathway in cancer cells through elevated aerobic glycolysis for energy supply and biomass. However, the mechanism of early stage metabolic dysregulation still remains unclear. 14-3-3ζ was found to be over-expressed in the early stages of breast disease and cancer (Atypical ductal hyperplasia and Ductal carcinoma in situ) and in >40% of breast cancer patients, correlating with poor patient prognosis. We found that 14-3-3ζ over-expression in non-transformed human mammary epithelial cells (HMECs), MCF10A and MCF12A, positively correlated with changes in the cellular glycolytic activity (increased glucose uptake, increased lactate production and reduced oxygen consumption). Additionally, 14-3-3ζ over-expression in HMECs induced soft agar colony formation and disorganized acini in three dimensional (3D) culture. Interestingly, we identified that lactate dehydrogenase A (LDHA) was up-regulated in these 14-3-3ζ overexpressing HMECs. LDHA knockdown in 14-3-3ζ overexpressing cells reduced aerobic glycolysis, decreased soft agar colonies and partially rescued the abnormal acinar structures, indicating LDHA upregulation contributed to 14-3-3ζ-mediated aerobic glycolysis and early transformation. Taken together, our data provide new insight into metabolic deregulation during the early stages of breast cancer transformation. Citation Format: Chia-Chi Chang, Jia Xu, Hai Wang, Chenyu Zhang, Jian Zhang, Sumaiyah K. Rehman, Ping Li, Dihua Yu. Increased glycolysis by 14-3-3ζ-mediated LDHA up-regulation contributes to transformation of early mammary epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5427. doi:10.1158/1538-7445.AM2013-5427