title: Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells.
abstract: The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1RhighCSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Fellow of the Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tominaga
authors.affiliation: Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kimura
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.|Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Murayama
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Matsubara
authors.affiliation: Department of Breast and Endocrine Surgery, Showa General Hospital, Kodaira, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kanauchi
authors.affiliation: Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Pathological Diagnosis, Showa General Hospital, Kodaira, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: E-I
authors.initials: EI
authors.lastname: Tsuji
authors.affiliation: Department of Surgery, Minami machida Hospital, Machida, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yano
authors.affiliation: Laboratory of Functional Genomics, Department of Medical Genome Sciences, Graduate School of Frontier Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sugano
authors.affiliation: Division of Molecular and Cellular Biology, Kobe University, Graduate School of Medicine, Kobe, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shimono
authors.affiliation: Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Division of Gene Regulation, Institute of Advanced Medical Research, Graduate School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Tada
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tojo
authors.affiliation: Laboratory of DNA information Analysis, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.|Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Gotoh
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D018874:Spheroids, Cellular; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C497453:ID1 protein, human; C035170:IGF2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016328:NF-kappa B; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D058539:Phosphatidylinositol 3-Kinase