NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype

Nat Commun. 2013;4:2299. doi: 10.1038/ncomms3299.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Binding Proteins / biosynthesis*
  • Calcium-Binding Proteins / metabolism
  • Carcinoma, Basal Cell / metabolism*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / metabolism
  • NF-kappa B / metabolism*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Notch / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Triple Negative Breast Neoplasms / metabolism*

Substances

  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jagged-1 Protein
  • Membrane Proteins
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase