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Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten
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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.
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“The IL-6–STAT3 pathway is involved in the epithelial–mesenchymal transition (EMT) (131, 132), tumor migration (133), cancer stemness (130, 134, 135) and the induction of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), two key players for angiogenesis (136–140).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [133]
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Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance
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BackgroundThe EASO New Investigator Award in Clinical Research 2021: Role of Chronotype in Obesity
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Cell lineage determinants as regulators of breast cancer metastasis
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“STAT3 is constitutively activated during various stages of breast carcinogenesis including metastasis [18].”
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Iezzi, M., Calogero, R., Spadaro, M., Musiani, P., Forni, G., & Cavallo, F. (2012) · doi:10.2174/978160805469511201010139 · Cited by 4
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“943), also referred to as CTEN, was reported to be linked to tumor progression and various cancer types including thymoma and colorectal, breast, and prostate cancers (Albasri et al. 2009; Barbieri et al. 2010; Katz et al. 2007; Li et al. 2010; Liao et al. 2009; Lo and Lo 2002; Sasaki et al. 2003).”
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“, constitutively active Signal Transducer and Activator of Transcription 3 (STAT3) upregulates TNS4 in both mouse model and human MCF10A cells, enhancing cell migration and invasion [146].”
Liu, L., Ma, C., Ji, J., Gao, R., & Li, D. (2025) · Oncology Letters · doi:10.3892/ol.2025.15006 · Cited by 2
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“In vivo, STAT3C enhances breast cancer cell migration and metastases in mouse mammary tumor virus (MMTV)-Neu transgenic mice [3,32].”
Self-citationQin, L., Cao, X., Kaneko, T., Voss, C., Liu, X., Wang, G., & Li, S. S. ‐. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101161 · Cited by 2
“Indeed, IL-6 has been identified as an important mediator of metastasis in breast cancer (38, 39), gastric cancer (40), and colorectal cancer (29, 41).”
BackgroundVectorisation de petits acides nucléiques par des lipopolyplexes : application au cancer du sein
Gosselin, M.-P. (2016) · theses.fr (ABES) · doi:10.70675/06376c4dz1796z471czb987z5262cb4428d7 · Cited by 1
“Constitutively activated STAT3 enhances metastasis of mammary tumors, and a STAT3 knockdown blocks breast cancer cell migration and metastasis (Barbieri et al., 2010).”
BackgroundThe role of C-terminal tensin-like (Cten) gene in cancer metastasis
Al-ghamdi, S., Alkwai, S., & Ilyas, M. (2018) · doi:10.24911/jbcgenetics/183-1531548689 · Cited by 1
“Two main pathways have been implicated that may regulate Cten, i.e., the EGFR/RAS/ MAPK pathway (21) and the STAT3 pathway (45).”
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Self-citationTumor intrinsic resistance to anti-programmed death 1
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“A number of clinical investigations have confirmed the role of activated STAT3 as an oncogene, mediating proteins that are involved in cancer cell proliferation and angiogenesis (24-26).”
BackgroundAn investigation into the role of C-terminal tensin-like protein (Cten) in melanomagenesis
Sjoestroem, A. C. (2013) · doi:10.14288/1.0165591
“Cten overexpression upon STAT3 activation has been found to result in increased cell migration, invasion and metastasis, and correlates with high tumour grade, aggressive and invasive inflammatory tumours, and lymph node metastasis (Barbieri et al., 2010; Pensa et al., 2012).”
BackgroundInfluential
Metadata
- Authors
- Barbieri, I., Pensa, S., Pannellini, T., Quaglino, E., Maritano, D., Demaria, M., Voster, A., Turkson, J., Cavallo, F., Watson, C. J., Provero, P., Musiani, P., & Poli, V.
- Affiliations
- University of Central Florida (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2010-03-14
- Volume
- 70
- Issue
- 6
- Pages
- 2558-2567
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2004465485
- Cited by
- 148
- References
- 64
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 12 · 2022: 6 · 2021: 4 · 2020: 10 · 2019: 6 · 2018: 12 · 2017: 7 · 2016: 10 · 2015: 9 · 2014: 17 · 2013: 11 · 2012: 16
- FWCI
- 6.95
- Type
- journal article
- Language
- en
- Open access
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- Journal of International Crisis and Risk Communication Research (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- Fondazione CRT
- Ministero dell'Università e della Ricerca
- National Cancer Institute (R01CA128865)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- STAT3, CTEN, mammary tumors, breast cancer, tumor cell migration, tumor invasion, metastasis, neu oncogene, mouse mammary tumor virus, cell-cell contact, interleukin-6, inflammation and cancer, oncogenic signaling
- MeSH terms
- Tensins, Animals, Breast Neoplasms, Cell Movement, Cell Nucleus, Female, Humans, Lung Neoplasms, Male, Mammary Neoplasms, Experimental, Mice, Transgenic, Microfilament Proteins, Phosphorylation, Transcription, Genetic, Up-Regulation, Erb-b2 Receptor Tyrosine Kinases, Cell Line, Tumor, STAT3 Transcription Factor, Mice
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