Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten
- 14 March 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (6), 2558-2567
- https://doi.org/10.1158/0008-5472.can-09-2840
Abstract
The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in tumors of different origin, but the molecular bases for STAT3 requirement are only partly understood. To evaluate the contribution of enhanced Stat3 activation in a controlled model system, we generated knock-in mice wherein a mutant constitutively active Stat3C allele replaces the endogenous wild-type allele. Stat3C could enhance the tumorigenic power of the rat Neu oncogene in mouse mammary tumor virus (MMTV)-Neu transgenic mice, triggering the production of earlier onset, more invasive mammary tumors. Tumor-derived cell lines displayed higher migration, invasion, and metastatic ability and showed disrupted distribution of cell-cell junction markers mediated by Stat3-dependent overexpression of the COOH terminal tensin-like (Cten) focal adhesion protein, which was also significantly upregulated in Stat3C mammary tumors. Importantly, the proinflammatory cytokine interleukin-6 could mediate Cten induction in MCF10 cells in an exquisitely Stat3-dependent way, showing that Cten upregulation is a feature of inflammation-activated Stat3. In light of the emerging pivotal role of Stat3 in connecting inflammation and cancer, our identification of Cten as a Stat3-dependent mediator of migration provides important new insights into the oncogenic role of Stat3, particularly in the breast.Keywords
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This publication has 37 references indexed in Scilit:
- The RhoU/Wrch1 Rho GTPase gene is a common transcriptional target of both the gp130/STAT3 and Wnt-1 pathwaysBiochemical Journal, 2009
- Genome-wide discovery of functional transcription factor binding sites by comparative genomics: The case of Stat3Proceedings of the National Academy of Sciences, 2009
- Inflammation and Cancer: IL-6 and STAT3 Complete the LinkCancer Cell, 2009
- Biology, prognosis and response to therapy of breast carcinomas according to HER2 scoreAnnals Of Oncology, 2008
- Twist Is Transcriptionally Induced by Activation of STAT3 and Mediates STAT3 Oncogenic FunctionJournal of Biological Chemistry, 2008
- STAT3 as a target for inducing apoptosis in solid and hematological tumorsCell Research, 2008
- A reciprocal tensin-3–cten switch mediates EGF-driven mammary cell migrationNature, 2007
- Selective chemical probe inhibitor of Stat3, identified through structure-based virtual screening, induces antitumor activityProceedings of the National Academy of Sciences, 2007
- Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironmentNature Reviews Immunology, 2007
- Rank products: a simple, yet powerful, new method to detect differentially regulated genes in replicated microarray experimentsFEBS Letters, 2004