Constitutively active Stat3 enhances neu-mediated migration and metastasis in mammary tumors via upregulation of Cten.
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.
Barbieri
Isaia
I
Molecular Biotechnology Center, Department of Genetics, Biology and Biochemistry, and Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Pensa
Sara
S
Pannellini
Tania
T
Quaglino
Elena
E
Maritano
Diego
D
Demaria
Marco
M
Voster
Alessandra
A
Turkson
James
J
Cavallo
Federica
F
Watson
Christine J
CJ
Provero
Paolo
P
Musiani
Piero
P
Poli
Valeria
V
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000070876:Tensins; D014158:Transcription, Genetic; D015854:Up-Regulation
D008840:Microfilament Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000070876:Tensins; C494087:Stat3 protein, mouse; C000603371:TNS4 protein, human; C000603372:Tns1 protein, rat; C000603393:Tns4 protein, mouse; C524056:Erbb2 protein, mouse