Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten

Isaia Barbieri, Sara Pensa, Tania Pannellini, Elena Quaglino, Diego Maritano, Marco Demaria, Alessandra Voster, James Turkson, Federica Cavallo, Christine J Watson, Paolo Provero, Piero Musiani, Valeria Poli

Research output: Contribution to journalArticleAcademicpeer-review

112 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2558-67
Number of pages10
JournalCancer Research
Volume70
Issue number6
DOIs
Publication statusPublished - 2010

Keywords

  • Animals
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus
  • Female
  • Humans
  • Lung Neoplasms
  • Male
  • Mammary Neoplasms, Experimental
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins
  • Phosphorylation
  • Receptor, ErbB-2
  • STAT3 Transcription Factor
  • Transcription, Genetic
  • Up-Regulation

Cite this