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      TGF‐β transactivates EGFR and facilitates breast cancer migration and invasion through canonical Smad3 and ERK/Sp1 signaling pathways

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          Abstract

          Transforming growth factor‐beta ( TGF‐β) functions as a potent proliferation inhibitor and apoptosis inducer in the early stages of breast cancer, yet promotes cancer aggressiveness in the advanced stages. The dual effect of TGF‐β on cancer development is known as TGF‐β paradox, and the remarkable functional conversion of TGF‐β is a pivotal and controversial phenomenon that has been widely investigated for decades. This phenomenon may be attributed to the cross talk between TGF‐β signaling and other pathways, including EGF receptor ( EGFR) signaling during cancer progression. However, the underlying mechanism by which TGF‐β shifts its role from a tumor suppressor to a cancer promoter remains elusive. In this study, TGF‐β is positively correlated with EGFR expression in breast cancer tissues, and a functional linkage is observed between TGF‐β signaling and EGFR transactivation in breast cancer cell lines. TGF‐β promotes the migration and invasion abilities of breast cancer cells, along with the increase in EGFR expression. EGFR is also essential for TGF‐β‐induced enhancement of these abilities of breast cancer cells. Canonical Smad3 signaling and ERK/Sp1 signaling pathways mediate TGF‐β‐induced EGFR upregulation. Hence, our study provided insights into a novel mechanism by which TGF‐β supports breast cancer progression.

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          The epidermal growth factor receptor pathway: a model for targeted therapy.

          The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.
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            The epidermal growth factor receptor family: biology driving targeted therapeutics.

            The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.
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              Regulation of EMT by TGFβ in cancer.

              Transforming growth factor-β (TGFβ) suppresses tumor formation since it inhibits cell growth and promotes apoptosis. However, in advanced cancers TGFβ elicits tumor promoting effects through its ability to induce epithelial-mesenchymal transition (EMT) which enhances invasiveness and metastasis; in addition, TGFβ exerts tumor promoting effects on non-malignant cells of the tumor, including suppression of immune surveillance and stimulation of angiogenesis. TGFβ promotes EMT by transcriptional and posttranscriptional regulation of a group of transcription factors that suppresses epithelial features, such as expression of components of cell junctions and polarity complexes, and enhances mesenchymal features, such as production of matrix molecules and several cytokines and growth factors that stimulate cell migration. The EMT program has certain similarities with the stem cell program. Inducers and effectors of EMT are interesting targets for the development of improved diagnosis, prognosis and therapy of cancer. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                feizhang03@tmu.edu.cn
                rniu@tmu.edu.cn
                Journal
                Mol Oncol
                Mol Oncol
                10.1002/(ISSN)1878-0261
                MOL2
                Molecular Oncology
                John Wiley and Sons Inc. (Hoboken )
                1574-7891
                1878-0261
                24 January 2018
                March 2018
                : 12
                : 3 ( doiID: 10.1002/mol2.2018.12.issue-3 )
                : 305-321
                Affiliations
                [ 1 ] Public Laboratory National Clinical Research Center for Cancer Tianjin Medical University Cancer Institute and Hospital China
                [ 2 ] Key Laboratory of Cancer Prevention and Therapy Tianjin China
                [ 3 ] Tianjin's Clinical Research Center for Cancer China
                [ 4 ] Key Laboratory of Breast Cancer Prevention and Therapy Ministry of Education Tianjin Medical University China
                Author notes
                [*] [* ] Correspondence

                F. Zhang and R. Niu, Public Laboratory, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China

                Fax/Tel.: +86‐22‐23340123 (ext. 6328) (FZ); +86‐22‐23340123 (ext. 6018) (RN)

                E‐mails: feizhang03@ 123456tmu.edu.cn (FZ); rniu@ 123456tmu.edu.cn (RN)

                Article
                MOL212162
                10.1002/1878-0261.12162
                5830653
                29215776
                6140bbe6-7448-451c-a628-16ff20288039
                © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 August 2017
                : 31 October 2017
                : 13 November 2017
                Page count
                Figures: 6, Tables: 4, Pages: 17, Words: 8619
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81372844
                Award ID: 81472474
                Award ID: 81772804
                Funded by: Tianjin Municipal Science and Technology Commission
                Award ID: 16JCYBJC25400
                Funded by: Changjiang Scholars and Innovative Research Team
                Award ID: IRT_14R40
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                mol212162
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:01.03.2018

                Oncology & Radiotherapy
                breast cancer,egf receptor,invasion,smad3,sp1,transforming growth factor‐β
                Oncology & Radiotherapy
                breast cancer, egf receptor, invasion, smad3, sp1, transforming growth factor‐β

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