A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1

Cancer Cell. 2013 May 13;23(5):647-59. doi: 10.1016/j.ccr.2013.03.012. Epub 2013 Apr 18.

Abstract

IκB kinase α (IKKα) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKKα and its activator, NF-κB-inducing kinase (NIK), support the expansion of tumor-initiating cells (TICs) that copurify with a CD24(med)CD49f(hi) population from premalignant ErbB2-expressing mammary glands. Upon activation, IKKα enters the nucleus, phosphorylates the cyclin-dependent kinase (CDK) inhibitor p27/Kip1, and stimulates its nuclear export or exclusion. Reduced p27 expression rescues mammary tumorigenesis in mice deficient in IKKα kinase activity and restores TIC self-renewal. IKKα is also likely to be involved in human breast cancer, where its expression shows an inverse correlation with metastasis-free survival, and its presence in the nucleus of invasive ductal carcinomas (IDCs) is associated with decreased nuclear p27 abundance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • CD24 Antigen / metabolism
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Female
  • I-kappa B Kinase / metabolism
  • I-kappa B Kinase / physiology*
  • Integrin alpha6 / metabolism
  • Mammary Neoplasms, Experimental / metabolism
  • Mice
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology*
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-2 / physiology*

Substances

  • CD24 Antigen
  • Cdkn1b protein, mouse
  • Integrin alpha6
  • Cyclin-Dependent Kinase Inhibitor p27
  • Erbb2 protein, mouse
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase
  • NF-kappa B kinase