title: 14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.
abstract: Transforming growth factor β (TGF-β) functions as a tumor suppressor in premalignant cells but as a metastasis promoter in cancer cells. The dichotomous functions of TGF-β are proposed to be dictated by different partners of its downstream effector Smads. However, the mechanism for the contextual changes of Smad partners remained undefined. Here, we demonstrate that 14-3-3ζ destabilizes p53, a Smad partner in premalignant mammary epithelial cells, by downregulating 14-3-3σ, thus turning off TGF-β's tumor suppression function. Conversely, 14-3-3ζ stabilizes Gli2 in breast cancer cells, and Gli2 partners with Smads to activate PTHrP and promote TGF-β-induced bone metastasis. The 14-3-3ζ-driven contextual changes of Smad partners from p53 to Gli2 may serve as biomarkers and therapeutic targets of TGF-β-mediated cancer progression.
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jia
authors: J
authors: Xu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors: Sunil
authors: S
authors: Acharya
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ozgur
authors: O
authors: Sahin
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Qingling
authors: Q
authors: Zhang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Yohei
authors: Y
authors: Saito
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jun
authors: J
authors: Yao
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Hai
authors: H
authors: Wang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Ping
authors: P
authors: Li
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors: Lin
authors: L
authors: Zhang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors: Frank J
authors: FJ
authors: Lowery
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Wen-Ling
authors: WL
authors: Kuo
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Yi
authors: Y
authors: Xiao
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Joe
authors: J
authors: Ensor
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Aysegul A
authors: AA
authors: Sahin
authors: Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Xiang H-F
authors: XH
authors: Zhang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
authors: Mien-Chie
authors: MC
authors: Hung
authors: Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd., 4070 Basel, Switzerland.
authors: Jitao David
authors: JD
authors: Zhang
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: dyu@mdanderson.org.
authors: Dihua
authors: D
authors: Yu
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics*; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D000075746:Zinc Finger Protein Gli2
chemical_list: D048948:14-3-3 Proteins; C082593:GLI2 protein, human; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D051785:Smad Proteins; C495901:TP53 protein, human; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C572235:YWHAZ protein, human; D000075746:Zinc Finger Protein Gli2