Abstract
High serum levels of IL-6 correlate with poor outcome in breast cancer patients. However, no data are available on the relationship between IL-6 and mammary stem/progenitor cells, which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in the MCF-7 breast cancer cell line and in primary human mammospheres (MS), multicellular structures enriched in stem/progenitor cells of the mammary gland. MS from node invasive breast carcinoma tissues expressed IL-6 mRNA at higher levels than did MS from matched non-neoplastic mammary glands. In addition, IL-6 mRNA was detected only in basal-like breast carcinoma tissues, an aggressive breast carcinoma variant showing stem cell features. IL-6 treatment triggered Notch-3-dependent upregulation of the Notch ligand Jagged-1 and promotion of MS and MCF-7-derived spheroid growth. Moreover, IL-6 induced Notch-3-dependent upregulation of the carbonic anhydrase IX gene and promoted a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, autocrine IL-6 signaling relied upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, these data support the hypothesis that IL-6 induces malignant features in Notch-3-expressing stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Autocrine Communication / drug effects
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Autocrine Communication / genetics
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Calcium-Binding Proteins
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Carbonic Anhydrase IX
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Carbonic Anhydrases / biosynthesis
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Carbonic Anhydrases / genetics
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Carcinoma, Ductal / genetics
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Carcinoma, Ductal / metabolism*
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Carcinoma, Ductal / pathology
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Cell Hypoxia / drug effects
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Cell Hypoxia / genetics
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Cell Line, Tumor
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Intercellular Signaling Peptides and Proteins
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Jagged-1 Protein
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Mammary Glands, Human / metabolism*
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Mammary Glands, Human / pathology
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Membrane Proteins
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Neoplasm Invasiveness
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasm Proteins / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Receptor, Notch3
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Receptors, Notch / genetics
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Receptors, Notch / metabolism
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Serrate-Jagged Proteins
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Spheroids, Cellular / metabolism*
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Spheroids, Cellular / pathology
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Stem Cells / metabolism*
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Stem Cells / pathology
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Antigens, Neoplasm
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Calcium-Binding Proteins
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IL6 protein, human
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Intercellular Signaling Peptides and Proteins
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Interleukin-6
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JAG1 protein, human
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Jagged-1 Protein
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Membrane Proteins
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NOTCH3 protein, human
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Receptor, Notch3
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Receptors, Notch
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Serrate-Jagged Proteins
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CA9 protein, human
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Carbonic Anhydrase IX
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Carbonic Anhydrases