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

ABSTRACT: I?B kinase ? (IKK?) activity is required for ErbB2-induced mammary tumorigenesis. Here, we show that IKK? and its activator, NF-?B-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, IKK? 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 IKK? kinase activity and restores TIC self-renewal. IKK? 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.

SUBMITTER: Zhang W 

PROVIDER: S-EPMC3981467 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature