The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion

Manran Liu, Toshiyuki Sakamaki, Mathew C. Casimiro, Nicole E. Willmarth, Andrew A. Quong, Xiaoming Ju, John Ojeifo, Xuanmao Jiao, Wen Shuz Yeow, Sanjay Katiyar, L. Andrew Shirley, David Joyce, Michael P. Lisanti, Christopher Albanese, Richard G. Pestell

    Research output: Contribution to journalArticlepeer-review

    Abstract

    The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB-dependent mammary tumorigenesis. ©2010 AACR.
    Original languageEnglish
    Pages (from-to)10464-10473
    Number of pages9
    JournalCancer Research
    Volume70
    Issue number24
    DOIs
    Publication statusPublished - 15 Dec 2010

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