Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression

// Chia-Chi Chang 1, 2 , Chenyu Zhang 1 , Qingling Zhang 1 , Ozgur Sahin 1 , Hai Wang 1 , Jia Xu 1 , Yi Xiao 1 , Jian Zhang 1 , Sumaiyah K. Rehman 1 , Ping Li 1 , Mien-Chie Hung 1, 2 , Fariba Behbod 3 , Dihua Yu 1, 2 1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Cancer Biology Program, Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA 3 Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA Correspondence to: Dihua Yu, e-mail: dyu@mdanderson.org Keywords: LDHA, 14-3-3ζ, glycolysis, cancer metabolism, breast cancer initiation Received: February 17, 2016     Accepted: April 16, 2016     Published: May 2, 2016 ABSTRACT Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby sustaining rapid proliferation. Recently, new evidence has emerged that metabolic dysregulation may occur at early-stages of neoplasia and critically contribute to cancer initiation. Here, our bioinformatics analysis of microarray data from early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of canonical glycolytic genes, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human mammary epithelial cells (hMECs) up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation. Knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Mechanistically, 14-3-3ζ overexpression activates the MEK-ERK-CREB axis, which subsequently up-regulates LDHA. In vivo , inhibiting the activated the MEK/ERK pathway in 14-3-3ζ-overexpressing hMEC-derived MCF10DCIS.COM lesions led to effective inhibition of tumor growth. Therefore, targeting the MEK/ERK pathway could be an effective strategy for intervention of 14-3-3ζ-overexpressing early breast lesions. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis and transcriptionally up-regulating LDHA, thereby contributes to human breast cancer initiation.