| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology, Pathobiology, and Genetics |
1 Department of Surgery, The Comprehensive Cancer Center, Duke University, Durham, North Carolina; Departments of 2 Molecular and Cellular Oncology, 3 Gastrointestinal Medical Oncology, 4 Breast Medical Oncology and 5 Graduate School of Biomedical Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 6 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; and 7 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3668; Fax: 713-794-0209; E-mail: mhung{at}mdanderson.org.
Aberrant epidermal growth factor receptor (EGFR) signaling is a major cause of tumor progression and metastasis; the underlying mechanisms, however, are not well understood. In particular, it remains elusive whether deregulated EGFR pathway is involved in epithelial-mesenchymal transition (EMT), an early event that occurs during metastasis of cancers of an epithelial origin. Here, we show that EGF induces EGFR-expressing cancer cells to undergo a transition from the epithelial to the spindle-like mesenchymal morphology. EGF reduced E-cadherin expression and increased that of mesenchymal proteins. In search of a downstream mediator that may account for EGF-induced EMT, we focused on transcription repressors of E-cadherin, TWIST, SLUG, and Snail and found that cancer cells express high levels of TWIST and that EGF enhances its expression. EGF significantly increases TWIST transcripts and protein in EGFR-expressing lines. Forced expression of EGFR reactivates TWIST expression in EGFR-null cells. TWIST expression is suppressed by EGFR and Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) inhibitors, but not significantly by those targeting phosphoinositide-3 kinase and MEK/ERK. Furthermore, constitutively active STAT3 significantly activates the TWIST promoter, whereas the JAK/STAT3 inhibitor and dominant-negative STAT3 suppressed TWIST promoter. Deletion/mutation studies further show that a 26-bp promoter region contains putative STAT3 elements required for the EGF-responsiveness of the TWIST promoter. Chromatin immunoprecipitation assays further show that EGF induces binding of nuclear STAT3 to the TWIST promoter. Immunohistochemical analysis of 130 primary breast carcinomas indicates positive correlations between non-nuclear EGFR and TWIST and between phosphorylated STAT3 and TWIST. Together, we report here that EGF/EGFR signaling pathways induce cancer cell EMT via STAT3-mediated TWIST gene expression. [Cancer Res 2007;67(19):9066–76]
This article has been cited by other articles:
![]() |
J. P. Smith, A. Pozzi, P. Dhawan, A. B. Singh, and R. C. Harris Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2 Am J Physiol Renal Physiol, May 1, 2009; 296(5): F957 - F965. [Abstract] [Full Text] [PDF] |
||||
![]() |
P.-L. Kuo, W.-C. Ni, E.-M. Tsai, and Y.-L. Hsu Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells Mol. Cancer Ther., May 1, 2009; 8(5): 1328 - 1339. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. B. Aggarwal, R.V. Vijayalekshmi, and B. Sung Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe Clin. Cancer Res., January 15, 2009; 15(2): 425 - 430. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Haddad, W. Choi, and D. J. McConkey Delta-Crystallin Enhancer Binding Factor 1 Controls the Epithelial to Mesenchymal Transition Phenotype and Resistance to the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Human Head and Neck Squamous Cell Carcinoma Lines Clin. Cancer Res., January 15, 2009; 15(2): 532 - 542. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. B. Kunnumakkara, A. S. Nair, B. Sung, M. K. Pandey, and B. B. Aggarwal Boswellic Acid Blocks Signal Transducers and Activators of Transcription 3 Signaling, Proliferation, and Survival of Multiple Myeloma via the Protein Tyrosine Phosphatase SHP-1 Mol. Cancer Res., January 1, 2009; 7(1): 118 - 128. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Blick, E. Widodo, H. Hugo, A. Fabra-Fres, R. Wafai, D. Gunasinghe, M. Waltham, M. Lenburg, R. Neve, D. Newgreen, et al. Abstract CN12-03: Epithelial-mesenchymal transition in human breast cancer progression: cancer stem cell attributes, dissemination, and dormancy Cancer Prevention Research, November 1, 2008; 1(7_MeetingAbstracts): CN12-03 - CN12-03. |
||||
![]() |
H.-W. Lo, X. Cao, H. Zhu, and F. Ali-Osman Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators Clin. Cancer Res., October 1, 2008; 14(19): 6042 - 6054. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Alix-Panabieres, S. Riethdorf, and K. Pantel Circulating Tumor Cells and Bone Marrow Micrometastasis Clin. Cancer Res., August 15, 2008; 14(16): 5013 - 5021. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Z. Cheng, W. Zhang, M. Sun, Q. Wang, D. Coppola, M. Mansour, L. Xu, C. Costanzo, J. Q. Cheng, and L.-H. Wang Twist Is Transcriptionally Induced by Activation of STAT3 and Mediates STAT3 Oncogenic Function J. Biol. Chem., May 23, 2008; 283(21): 14665 - 14673. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Shen, D. S. Hirsch, C. A. Sasiela, and W. J. Wu Cdc42 Regulates E-cadherin Ubiquitination and Degradation through an Epidermal Growth Factor Receptor to Src-mediated Pathway J. Biol. Chem., February 22, 2008; 283(8): 5127 - 5137. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |