title: ErbB receptor tyrosine kinase/NF-κB signaling controls mammosphere formation in human breast cancer.
abstract: Breast cancer is one of the most common cancers in humans. However, our understanding of the cellular and molecular mechanisms underlying tumorigenesis in breast tissues is limited. Here, we identified a molecular mechanism that controls the ability of breast cancer cells to form multicellular spheroids (mammospheres). We found that heregulin (HRG), a ligand for ErbB3, induced mammosphere formation of a breast cancer stem cell (BCSC)-enriched population as well as in breast cancer cell lines. HRG-induced mammosphere formation was reduced by treatment with inhibitors for phosphatidyl inositol 3-kinase (PI3K) or NF-κB and by expression of IκBα-Super Repressor (IκBαSR), a dominant-negative inhibitor for NF-κB. Moreover, the overexpression of IκBαSR in breast cancer cells inhibited tumorigenesis in NOD/SCID mice. Furthermore, we found that the expression of IL8, a regulator of self-renewal in BCSC-enriched populations, was induced by HRG through the activation of the PI3K/NF-κB pathway. These findings illustrate that HRG/ErbB3 signaling appears to maintain mammosphere formation through a PI3K/NF-κB pathway in human breast cancer.
authors.affiliation: Division of Systems Biomedical Technology, Institute of Medical Science,  University of Tokyo, Minato-ku, Tokyo 108-8639,  Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hinohara
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hajime
authors.initials: H
authors.lastname: Kanauchi
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Shimizu
authors.forename: Kotoe
authors.initials: K
authors.lastname: Nishioka
authors.forename: Ei-ichi
authors.initials: E
authors.lastname: Tsuji
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Tada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ogawa
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Inoue
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.forename: Noriko
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D016209:Interleukin-8; D016328:NF-kappa B; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases