Title

Constitutively Active Stat3 Enhances Neu-Mediated Migration And Metastasis In Mammary Tumors Via Upregulation Of Cten

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 knockin 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. ©2010 AACR.

Publication Date

3-15-2010

Publication Title

Cancer Research

Volume

70

Issue

6

Number of Pages

2558-2567

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1158/0008-5472.CAN-09-2840

Socpus ID

77950211267 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/77950211267

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