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

SummaryIκB 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.

► ErbB2-induced mammary tumors originate from basal and luminal epithelial cells
► NIK/IKKα module expands ErbB2-induced basal TICs
► IKKα directly phosphorylates p27 and drives its nuclear exclusion
► IKKα mRNA correlates with increased metastasis in human breast cancer