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

The transcription factor STAT3 is constitutively activated in tumors of different origin but the molecular bases for STAT3 requirement are only partly understood. In order to evaluate the contribution of enhanced Stat3 activation in a controlled model system, we generated knock/in mice where a mutant constitutively active Stat3C allele replaces the endogenous wild type allele. Stat3C could enhance the tumorigenic power of the rat Neu oncogene in 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 over-expression of the C-Terminal Tensin-like (Cten) focal adhesion protein, which was also significantly upregulated in Stat3C mammary tumors. Importantly, the pro-inflammatory cytokine IL-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 the 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.