Abstract
Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1β (IL-1β)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1β maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1β expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Breast Neoplasms / drug therapy
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Breast Neoplasms / immunology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cadherins / genetics
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Cadherins / metabolism
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Cell Communication
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Cell Differentiation
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Cell Line, Tumor
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Cell Plasticity
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Cell Proliferation
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Female
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Humans
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Inflammation / immunology
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Inflammation / metabolism*
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Inflammation / pathology
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Inflammation / prevention & control
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism*
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Interleukin-1beta / pharmacology
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Lung Neoplasms / immunology
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Lung Neoplasms / metabolism*
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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Lymphatic Metastasis
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Mice, Nude
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / metabolism*
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Myeloid Cells / pathology
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Signal Transduction
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Time Factors
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Tumor Microenvironment*
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Xenograft Model Antitumor Assays
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Zinc Finger E-box-Binding Homeobox 1 / genetics
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Zinc Finger E-box-Binding Homeobox 1 / metabolism
Substances
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Anti-Inflammatory Agents
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Antigens, CD
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CDH1 protein, human
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Cadherins
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IL1B protein, human
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IL1B protein, mouse
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Interleukin-1beta
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ZEB1 protein, human
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Zinc Finger E-box-Binding Homeobox 1