A NIK-IKKα Module Expands ErbB2-Induced Tumor-Initiating Cells by Stimulating Nuclear Export of p27/Kip1

Weizhou Zhang, Wei Tan, Xuefeng Wu, Maxim Poustovoitov, Amy Strasner, Wei Li, Nicholas Borcherding, Majid Ghassemian, Michael Karin

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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 CD24medCD49fhi 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.

Original languageEnglish
Pages (from-to)647-659
Number of pages13
JournalCancer Cell
Volume23
Issue number5
DOIs
StatePublished - 13 May 2013
Externally publishedYes

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