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Cancer Cell. 2015 Feb 9;27(2):177-92. doi: 10.1016/j.ccell.2014.11.025.

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.

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
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.
3
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
6
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.
7
Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Ltd., 4070 Basel, Switzerland.
8
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.

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.

PMID:
25670079
PMCID:
PMC4325275
DOI:
10.1016/j.ccell.2014.11.025
[Indexed for MEDLINE]
Free PMC Article

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