title: Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression.
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.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Program, Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Sahin
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sumaiyah K
authors.initials: SK
authors.lastname: Rehman
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Program, Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Fariba
authors.initials: F
authors.lastname: Behbod
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Program, Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Dihua
authors.initials: D
authors.lastname: Yu
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006019:Glycolysis; D064593:Heterografts; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis*; D000080864:Lactate Dehydrogenase 5; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D015854:Up-Regulation
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D007527:Isoenzymes; C572235:YWHAZ protein, human; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
keywords: 14-3-3ζ; LDHA; breast cancer initiation; cancer metabolism; glycolysis