Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten

    Authors

    I. Barbieri; S. Pensa; T. Pannellini; E. Quaglino; D. Maritano; M. Demaria; A. Voster; J. Turkson; F. Cavallo; C. J. Watson; P. Provero; P. Musiani;V. Poli

    Comments

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    Abbreviated Journal Title

    Cancer Res.

    Keywords

    ANCHORAGE-INDEPENDENT GROWTH; MESSENGER-RNA EXPRESSION; HUMAN; BREAST-CANCER; EPITHELIAL-CELLS; SIGNAL TRANSDUCER; GENE-EXPRESSION; ACTIVATION; PROGRESSION; ONCOGENE; TUMORIGENESIS; Oncology

    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. Cancer Res; 70(6); 2558-67. (C)2010 AACR.

    Journal Title

    Cancer Research

    Volume

    70

    Issue/Number

    6

    Publication Date

    1-1-2010

    Document Type

    Article

    Language

    English

    First Page

    2558

    Last Page

    2567

    WOS Identifier

    WOS:000278485900043

    ISSN

    0008-5472

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