Abstract
Patients with triple-negative breast cancer display the highest rates of early relapse of all patients with breast cancer. The basal-like subtype, a subgroup of triple-negative breast cancer, exhibits high levels of constitutively active NF-κB signalling. Here we show that NF-κB activation, induced by inflammatory cytokines or by epigenetically dysregulated NIK expression, cell-autonomously upregulates JAG1 expression in non-cancer stem cells. This upregulation stimulates NOTCH signalling in cancer stem cells in trans, leading to an expansion of cancer stem cell populations. Among breast cancers, the NF-κB-dependent induction of JAG1 and the NOTCH-dependent expansion of the cancer stem cell population occur only in the basal-like subtype. Collectively, our results indicate that NF-κB has a non-cell-autonomous role in regulating cancer stem cell populations by forming intratumoural microenvironments composed of JAG1-expressing non-cancer stem cells with a basal-like subtype.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium-Binding Proteins / biosynthesis*
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Calcium-Binding Proteins / metabolism
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Carcinoma, Basal Cell / metabolism*
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Intercellular Signaling Peptides and Proteins / biosynthesis*
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Intercellular Signaling Peptides and Proteins / metabolism
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Jagged-1 Protein
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Membrane Proteins / biosynthesis*
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Membrane Proteins / metabolism
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NF-kappa B / metabolism*
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NF-kappaB-Inducing Kinase
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Neoplasm Recurrence, Local / metabolism
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Neoplastic Stem Cells / metabolism*
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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RNA, Small Interfering
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Receptors, Notch / metabolism
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Serrate-Jagged Proteins
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Signal Transduction
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Triple Negative Breast Neoplasms / metabolism*
Substances
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Calcium-Binding Proteins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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NF-kappa B
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RNA, Small Interfering
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Receptors, Notch
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Serrate-Jagged Proteins
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Protein Serine-Threonine Kinases