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

Jia Xu; Sunil Acharya; Ozgur Sahin; Qingling Zhang; Yohei Saito; Jun Yao; Hai Wang; Ping Li; Lin Zhang; Frank J. Lowery; Wen Ling Kuo; Yi Xiao; Joe Edward Ensor, Jr.; Aysegul A. Sahin; Xiang H F Zhang; Mien Chie Hung; Jitao David Zhang; Dihua Yu

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

Jia Xu, Sunil Acharya, Ozgur Sahin, Qingling Zhang, Yohei Saito, Jun Yao, Hai Wang, Ping Li, Lin Zhang, Frank J. Lowery, Wen Ling Kuo, Yi Xiao, Joe Edward Ensor, Jr., Aysegul A. Sahin, Xiang H F Zhang, Mien Chie Hung, Jitao David Zhang, Dihua Yu

Research output: Contribution to journal › Article › peer-review

140 Scopus citations

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.

Original language	English (US)
Pages (from-to)	177-192
Number of pages	16
Journal	Cancer Cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2014.11.025
State	Published - Feb 9 2015

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2014.11.025

Cite this

Xu, J., Acharya, S., Sahin, O., Zhang, Q., Saito, Y., Yao, J., Wang, H., Li, P., Zhang, L., Lowery, F. J., Kuo, W. L., Xiao, Y., Ensor, Jr., J. E., Sahin, A. A., Zhang, X. H. F., Hung, M. C., Zhang, J. D., & Yu, D. (2015). 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. Cancer Cell, 27(2), 177-192. https://doi.org/10.1016/j.ccell.2014.11.025

Xu, J, Acharya, S, Sahin, O, Zhang, Q, Saito, Y, Yao, J, Wang, H, Li, P, Zhang, L, Lowery, FJ, Kuo, WL, Xiao, Y, Ensor, Jr., JE, Sahin, AA, Zhang, XHF, Hung, MC, Zhang, JD & Yu, D 2015, '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', Cancer Cell, vol. 27, no. 2, pp. 177-192. https://doi.org/10.1016/j.ccell.2014.11.025

@article{443707f420c94ad0a39cbeb576b72f3b,

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.",

author = "Jia Xu and Sunil Acharya and Ozgur Sahin and Qingling Zhang and Yohei Saito and Jun Yao and Hai Wang and Ping Li and Lin Zhang and Lowery, {Frank J.} and Kuo, {Wen Ling} and Yi Xiao and {Ensor, Jr.}, {Joe Edward} and Sahin, {Aysegul A.} and Zhang, {Xiang H F} and Hung, {Mien Chie} and Zhang, {Jitao David} and Dihua Yu",

note = "Funding Information: This work was supported by NIH grants P30-CA 16672 (MDACC), PO1-CA099031 project 4 (D.Y.), and RO1-CA112567-07 (D.Y.); Susan G. Komen Foundation grant KG091020 (D.Y.); Cancer Prevention Research Institute of Texas grant RP100726 (D.Y.); METAvivor research grant (D.Y.); DOD Pre-doctoral Fellowship W81XWH-10-1-0238 (J.X.); and a Sowell-Huggins Professorship (D.Y.) and Pre-doctoral Fellowship in Cancer Research (L.Z.). D.Y. is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at MD Anderson Cancer Center. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = feb,

day = "9",

doi = "10.1016/j.ccell.2014.11.025",

language = "English (US)",

volume = "27",

pages = "177--192",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - 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

AU - Xu, Jia

AU - Acharya, Sunil

AU - Sahin, Ozgur

AU - Zhang, Qingling

AU - Saito, Yohei

AU - Yao, Jun

AU - Wang, Hai

AU - Li, Ping

AU - Zhang, Lin

AU - Lowery, Frank J.

AU - Kuo, Wen Ling

AU - Xiao, Yi

AU - Ensor, Jr., Joe Edward

AU - Sahin, Aysegul A.

AU - Zhang, Xiang H F

AU - Hung, Mien Chie

AU - Zhang, Jitao David

AU - Yu, Dihua

N1 - Funding Information: This work was supported by NIH grants P30-CA 16672 (MDACC), PO1-CA099031 project 4 (D.Y.), and RO1-CA112567-07 (D.Y.); Susan G. Komen Foundation grant KG091020 (D.Y.); Cancer Prevention Research Institute of Texas grant RP100726 (D.Y.); METAvivor research grant (D.Y.); DOD Pre-doctoral Fellowship W81XWH-10-1-0238 (J.X.); and a Sowell-Huggins Professorship (D.Y.) and Pre-doctoral Fellowship in Cancer Research (L.Z.). D.Y. is the Hubert L. & Olive Stringer Distinguished Chair in Basic Science at MD Anderson Cancer Center. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/2/9

Y1 - 2015/2/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84922828531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922828531&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2014.11.025

DO - 10.1016/j.ccell.2014.11.025

M3 - Article

C2 - 25670079

AN - SCOPUS:84922828531

SN - 1535-6108

VL - 27

SP - 177

EP - 192

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this