Journal Article

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

Ouzounova, M, Malik, F, Korkaya, H, Baker, T L, Wicha, M S, Paulson, A K, Quraishi, A A, Liu, S, Davis, A, Kim, G, Thomas, D G, Esen, E S, D'Angelo, R C, Kleer, C G, Tawakkol, N, Clouthier, S G, Korkaya, S, Prat, A

2015

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Publishing Group [1987-....]
• Subject: 631/67/1347 / 631/67/581 / 631/67/71 / 692/420/755 / Analysis / Animal models / Animals / Apoptosis / Breast cancer / Cancer therapies / Carcinogenesis / Carcinoma / Carcinoma, Intraductal, Noninfiltrating - genetics / Carcinoma, Intraductal, Noninfiltrating - pathology / Care and treatment / Cell activation / Cell Biology / Cell culture / Cell self-renewal / Cytokines / Development and progression / Female / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Human Genetics / Humans / Inflammation / Inflammation - genetics / Inflammation - pathology / Interleukin 6 / Interleukin 6 receptors / Interleukin-6 - metabolism / Internal Medicine / Invasiveness / Life Sciences / Medicine / Medicine & Public Health / Mesenchyme / Metastases / Mice / Mutation / Oncology / original-article / p53 Protein / Proteolysis / PTEN Phosphohydrolase - genetics / PTEN protein / Receptors, Interleukin-6 - metabolism / Signal transduction / SOCS-3 protein / Stat3 protein / Stem cell transplantation / Stem cells / Suppressor of Cytokine Signaling 3 Protein / Suppressor of Cytokine Signaling Proteins - genetics / Suppressor of Cytokine Signaling Proteins - metabolism / Transformed cells / Triple Negative Breast Neoplasms - genetics / Triple Negative Breast Neoplasms - pathology / Tumor cells / Tumor Suppressor Protein p53 - genetics / Tumors / Xenograft Model Antitumor Assays / Xenografts