SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model
| Autor: | Suling Liu, Max S. Wicha, Nader Tawakkol, Fayaz Malik, Trenton L. Baker, Amanda K. Paulson, Celina G. Kleer, Ahmed A. Quraishi, Aleix Prat, Hasan Korkaya, Gwangil Kim, Elif Serap Esen, Dafydd G. Thomas, Sumeyye Korkaya, Shawn G. Clouthier, Maria Ouzounova, Rosemarie C. D'Angelo, April Davis |
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| Přispěvatelé: | University of Michigan [Ann Arbor], University of Michigan System |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Carcinogenesis [SDV]Life Sciences [q-bio] Suppressor of Cytokine Signaling Proteins Triple Negative Breast Neoplasms medicine.disease_cause Molecular oncology Article Metastasis Mice 03 medical and health sciences 0302 clinical medicine Circulating tumor cell Cancer stem cell Genetics medicine Animals Humans PTEN skin and connective tissue diseases Molecular Biology ComputingMilieux_MISCELLANEOUS 030304 developmental biology Inflammation 0303 health sciences biology Interleukin-6 PTEN Phosphohydrolase medicine.disease Receptors Interleukin-6 Xenograft Model Antitumor Assays 3. Good health Gene Expression Regulation Neoplastic Carcinoma Intraductal Noninfiltrating Suppressor of Cytokine Signaling 3 Protein 030220 oncology & carcinogenesis Cancer research biology.protein Female Tumor Suppressor Protein p53 Stem cell |
| Zdroj: | Oncogene Oncogene, Nature Publishing Group, 2015, 34 (6), pp.671-680. ⟨10.1038/onc.2014.4⟩ |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2014.4 |
| Popis: | Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN, are strongly associated with triple negative breast cancer. In addition, these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors, which currently lacks molecularly targeted therapies. |
| Databáze: | OpenAIRE |
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