Journal article
A NIK-IKKα Module Expands ErbB2-Induced Tumor-Initiating Cells by Stimulating Nuclear Export of p27/Kip1
Cancer cell, Vol.23(5), pp.647-659
05/13/2013
DOI: 10.1016/j.ccr.2013.03.012
PMCID: PMC3981467
PMID: 23602409
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.
► 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
Details
- Title: Subtitle
- A NIK-IKKα Module Expands ErbB2-Induced Tumor-Initiating Cells by Stimulating Nuclear Export of p27/Kip1
- Creators
- Weizhou Zhang - 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, USAWei Tan - 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, USAXuefeng Wu - 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, USAMaxim Poustovoitov - 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, USAAmy Strasner - 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, USAWei Li - 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, USANicholas Borcherding - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USAMajid Ghassemian - Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0723, USAMichael Karin - 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
- Resource Type
- Journal article
- Publication Details
- Cancer cell, Vol.23(5), pp.647-659
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.ccr.2013.03.012
- PMID
- 23602409
- PMCID
- PMC3981467
- ISSN
- 1535-6108
- eISSN
- 1878-3686
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: CA127923, CA158055, T32CA121938, KG111506, KG080649; DOI: 10.13039/100000869, name: Susan G. Komen for the Cure, award: CA127923, CA158055, T32CA121938, KG111506, KG080649; DOI: 10.13039/100000048, name: American Cancer Society, award: CA127923, CA158055, T32CA121938, KG111506, KG080649
- Language
- English
- Date published
- 05/13/2013
- Academic Unit
- Dermatology; Radiation Oncology
- Record Identifier
- 9984083264902771
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