title: A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1.
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.
authors.affiliation: Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.forename: Maxim
authors.initials: M
authors.lastname: Poustovoitov
authors.forename: Amy
authors.initials: A
authors.lastname: Strasner
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Nicholas
authors.initials: N
authors.lastname: Borcherding
authors.forename: Majid
authors.initials: M
authors.lastname: Ghassemian
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D051927:CD24 Antigen / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D039503:Integrin alpha6 / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051927:CD24 Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051550:I-kappa B Kinase; D039503:Integrin alpha6; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000097782:NF-kappaB-Inducing Kinase; C493961:Cdkn1b protein, mouse; C524056:Erbb2 protein, mouse