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.

Academic Article

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

    Published In

  • Cancer Cell  Journal

    • Keywords

  • 14-3-3 Proteins, Bone Neoplasms, Breast Neoplasms, Cell Line, Tumor, Epithelial-Mesenchymal Transition, Female, Humans, Kruppel-Like Transcription Factors, Molecular Targeted Therapy, Neoplasm Metastasis, Nuclear Proteins, Promoter Regions, Genetic, Smad Proteins, Transforming Growth Factor beta, Tumor Suppressor Protein p53, Zinc Finger Protein Gli2

    • Digital Object Identifier (doi)

    Author List

  • Xu J; Acharya S; Sahin O; Zhang Q; Saito Y; Yao J; Wang H; Li P; Zhang L; Lowery FJ

    • Start Page

  • 177

    • End Page

  • 192

    • Volume

  • 27

    • Issue

  • 2