title: SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model.
abstract: 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.
authors: 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.
authors: G
authors: G
authors: Kim
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: M
authors: M
authors: Ouzounova
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: A A
authors: AA
authors: Quraishi
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: A
authors: A
authors: Davis
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: N
authors: N
authors: Tawakkol
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: S G
authors: SG
authors: Clouthier
authors: 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.
authors: F
authors: F
authors: Malik
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: A K
authors: AK
authors: Paulson
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: R C
authors: RC
authors: D'Angelo
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: S
authors: S
authors: Korkaya
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: T L
authors: TL
authors: Baker
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: E S
authors: ES
authors: Esen
authors: Translational Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: A
authors: A
authors: Prat
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: S
authors: S
authors: Liu
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
authors: C G
authors: CG
authors: Kleer
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
authors: D G
authors: DG
authors: Thomas
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: M S
authors: MS
authors: Wicha
authors: Comprehensive Cancer Center, Department of Internal medicine, University of Michigan, Ann Arbor, MI, USA.
authors: H
authors: 0000000207195862
authors: H
authors: Korkaya
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human