IL-6 Triggers Malignant Features in Mammospheres From Human Ductal Breast Carcinoma and Normal Mammary Gland

J Clin Invest. 2007 Dec;117(12):3988-4002. doi: 10.1172/JCI32533.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / genetics
  • Autocrine Communication / drug effects
  • Autocrine Communication / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Calcium-Binding Proteins
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / biosynthesis
  • Carbonic Anhydrases / genetics
  • Carcinoma, Ductal / genetics
  • Carcinoma, Ductal / metabolism*
  • Carcinoma, Ductal / pathology
  • Cell Hypoxia / drug effects
  • Cell Hypoxia / genetics
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Jagged-1 Protein
  • Mammary Glands, Human / metabolism*
  • Mammary Glands, Human / pathology
  • Membrane Proteins
  • Neoplasm Invasiveness
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Receptor, Notch3
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Serrate-Jagged Proteins
  • Spheroids, Cellular / metabolism*
  • Spheroids, Cellular / pathology
  • Stem Cells / metabolism*
  • Stem Cells / pathology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Antigens, Neoplasm
  • Calcium-Binding Proteins
  • IL6 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH3 protein, human
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Receptor, Notch3
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases