SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model.

Autor:	Kim G; 1] Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA [2] Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam 463-712, Gyeonggi, Republic of Korea., Ouzounova M; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Quraishi AA; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Davis A; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Tawakkol N; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Clouthier SG; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Malik F; 1] Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA [2] Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Jammu, India., Paulson AK; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., D'Angelo RC; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Korkaya S; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Baker TL; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Esen ES; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Prat A; Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Liu S; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Kleer CG; Department of Pathology, University of Michigan Medical School, Ann Arbor, USA., Thomas DG; Department of Pathology, University of Michigan Medical School, Ann Arbor, USA., Wicha MS; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA., Korkaya H; Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
Jazyk:	angličtina
Zdroj:	Oncogene [Oncogene] 2015 Feb 05; Vol. 34 (6), pp. 671-80. Date of Electronic Publication: 2014 Feb 17.
DOI:	10.1038/onc.2014.4
Abstrakt:	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:	MEDLINE
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