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 language | English |
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Pages (from-to) | 2558-67 |
Number of pages | 10 |
Journal | Cancer Research |
Volume | 70 |
Issue number | 6 |
DOIs | |
Publication status | Published - 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