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

作者：Zhang, Weizhou; Tan, Wei; Wu, Xuefeng; Poustovoitov, Maxim; Strasner, Amy; Li, Wei; Borcherding, Nicholas; Ghassemian, Majid; Karin, Michael^*

来源：Cancer Cell, 2013, 23(5): 647-659.

DOI：10.1016/j.ccr.2013.03.012

• MAMMARY EPITHELIAL-CELLS
• NF-KAPPA-B
• KINASE INHIBITOR P27(KIP1)
• CANCER METASTASIS
• SELF-RENEWAL
• CYCLIN D1
• GLAND MORPHOGENESIS
• TRANSGENIC MICE
• STEM
• EXPRESSION

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

• 出版日期2013-5-13