title: The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion.
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.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Manran
authors.initials: M
authors.lastname: Liu
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakamaki
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Casimiro
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Willmarth
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Quong
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Ju
authors.forename: John
authors.initials: J
authors.lastname: Ojeifo
authors.forename: Xuanmao
authors.initials: X
authors.lastname: Jiao
authors.forename: Wen-Shuz
authors.initials: WS
authors.lastname: Yeow
authors.forename: Sanjay
authors.initials: S
authors.lastname: Katiyar
authors.forename: L Andrew
authors.initials: LA
authors.lastname: Shirley
authors.forename: David
authors.initials: D
authors.lastname: Joyce
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Christopher
authors.initials: C
authors.lastname: Albanese
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D014162:Transfection
chemical_list: D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C000606205:Nfkbia protein, mouse