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      Tipping the balance between good and evil: aberrant 14-3-3ζ expression drives oncogenic TGF-β signaling in metastatic breast cancers

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      Author(s): ,
      Publication date (Electronic):
      Journal: Breast Cancer Research : BCR
      Publisher: BioMed Central

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          Abstract

          Transforming growth factor beta (TGF-β) readily suppresses the development of early-stage breast cancers, an activity that gives way to tumor promotion in their late-stage counterparts. The molecular mechanisms underlying this mysterious switch in TGF-β function remain murky. In addressing this conundrum, Xu et al. observed aberrant 14-3-3ζ expression to prevent the formation of tumor-suppressive Smad2/3:p53 complexes, while simultaneously driving the generation of oncogenic Smad2/3:Gli2 complexes. Once formed, Smad2/3:Gli2 complexes stimulate the expression of parathyroid hormone-related protein necessary for breast cancer metastasis to bone. This viewpoint highlights 14-3-3ζ as an essential driver of oncogenic signaling by Smad2/3 and TGF-β in metastatic breast cancers.

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          Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response.

          Michael Yaffe, H. Reinhardt (2013)
          Coordinated progression through the cell cycle is a complex challenge for eukaryotic cells. Following genotoxic stress, diverse molecular signals must be integrated to establish checkpoints specific for each cell cycle stage, allowing time for various types of DNA repair. Phospho-Ser/Thr-binding domains have emerged as crucial regulators of cell cycle progression and DNA damage signalling. Such domains include 14-3-3 proteins, WW domains, Polo-box domains (in PLK1), WD40 repeats (including those in the E3 ligase SCF(βTrCP)), BRCT domains (including those in BRCA1) and FHA domains (such as in CHK2 and MDC1). Progress has been made in our understanding of the motif (or motifs) that these phospho-Ser/Thr-binding domains connect with on their targets and how these interactions influence the cell cycle and DNA damage response.
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            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 … (2015)
            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.
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              Transforming growth factor-β and the hallmarks of cancer.

              Maozhen Tian, Jason R Neil, William Schiemann (2011)
              Tumorigenesis is in many respects a process of dysregulated cellular evolution that drives malignant cells to acquire six phenotypic hallmarks of cancer, including their ability to proliferate and replicate autonomously, to resist cytostatic and apoptotic signals, and to induce tissue invasion, metastasis, and angiogenesis. Transforming growth factor-β (TGF-β) is a potent pleiotropic cytokine that functions as a formidable barrier to the development of cancer hallmarks in normal cells and tissues. Paradoxically, tumorigenesis counteracts the tumor suppressing activities of TGF-β, thus enabling TGF-β to stimulate cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant cells overcome the cytostatic actions of TGF-β, and of how TGF-β stimulates the acquisition of cancer hallmarks by developing and progressing human cancers. Here we review the molecular and cellular mechanisms that underlie the ability of TGF-β to mediate tumor suppression in normal cells, and conversely, to facilitate cancer progression and disease dissemination in malignant cells. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Chevaun D. Morrison: cdm58@case.edu
                William P. Schiemann: +1 216 368 5763 , wps20@case.edu
                Journal
                Journal ID (nlm-ta): Breast Cancer Res
                Title: Breast Cancer Research : BCR
                Publisher: BioMed Central (London )
                ISSN (Print): 1465-5411
                ISSN (Electronic): 1465-542X
                Publication date (Electronic): 11 July 2015
                Publication date PMC-release: 11 July 2015
                Publication date (Print): 2015
                Volume: 17
                Electronic Location Identifier: 92
                Affiliations
                Case Comprehensive Cancer Center, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106 USA
                Article
                Publisher ID: 603
                DOI: 10.1186/s13058-015-0603-2
                PMC ID: 4702299
                PubMed ID: 26160166
                SO-VID: 6ee8a2b1-2e43-4431-b109-eb939fc8bfa1
                Copyright © © Morrison and Schiemann. 2015
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: CA129359
                Award ID: CA177069
                Award Recipient :
                Categories
                Subject: Viewpoint
                Custom metadata
                issue-copyright-statement © The Author(s) 2015

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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