Molecular mechanisms of maintenance of cancer stem cells in malignant breast cancers

• Project/Area Number: 26290036
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: Inoue Jun-ichiro 東京大学, 医科学研究所, 教授 (70176428)
• Research Collaborator: YAMAMOTO Mizuki 東京大学, 医科学研究所, 特任助教 (90750365)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 癌 / シグナル伝達

Outline of Final Research Achievements

Involvement of the NF-kB-JAG1-NOTCH pathway in the maintenance of cancer stem cells, which was demonstrated using cultured breast cancer cell lines, is shown to be happened in breast cancer cells prepared from specimens. These results suggest that the NF-kB-JAG1-NOTCH pathway could be a target for therapy. In basal-like breast cancer cell lines, epithelial and mesenchymal cell populations are demonstrated to co-exist at a constant ratio due to the mutual interactions that regulate both epithelial-mesenchymal transition and mesenchymal-epithelial transition. Similar analyses of breast cancer specimens reveal involvement of such mutual interactions in tumor metastasis and cancer stem cell maintenance in vivo.

Research Products

• [Journal Article] Epistasis between TIFAB and miR-146a, neighboring genes in del(5q) MDS. (2017)
  • Author(s): Varney, M., Choi, K., Bolanos, L., Christie, S., Fang, J., Grimes, L., Maciejewski, J., Inoue, J. and Starczynowski D
  • Journal Title: Leukemia Volume: 31 Issue: 2 Pages: 491-495
  • DOI: 10.1038/leu.2016.276
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HTLV-1 Tax induces formation of the active macromolecular IKK complex by generating Lys63- and Met1-linked hybrid polyubiquitin chains. (2017)
  • Author(s): Shibata Y, Tokunaga F, Goto E, Komatsu G, Gohda J, Saeki Y, Tanaka K, Takahashi H, Sawasaki T, Inoue S, Oshiumi H, Seya T, Nakano H, Tanaka Y, Iwai K, and Inoue J.
  • Journal Title: PLoS Pathog. Volume: 13 Issue: 12 Pages: e1006162-e1006162
  • DOI: 10.1371/journal.ppat.1006162
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer. (2017)
  • Author(s): Yamamoto, M., Sakane, K., Tominaga, K., Gotoh, N., Niwa, T., Kikuchi, Y., Tada, K., Goshima, N., Semba, K. and Inoue, J.
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 6 Pages: 1210-1222
  • DOI: 10.1111/cas.13246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrative Network Analysis Combined with Quantitative Phosphoproteomics Reveals TGFBR2 as a Novel Regulator of Glioblastoma Stem Cell Properties (2016)
  • Author(s): Narushima Y, Kozuka-Hata H, Koyama-Nasu R, Tsumoto K, Inoue J, Akiyama T & Oyama M.
  • Journal Title: Molecular and Cellular Proteomics Volume: 15 Issue: 3 Pages: 1017-1031
  • DOI: 10.1074/mcp.m115.049999
  • Peer Reviewed / Open Access
• [Journal Article] Quantitative phosphoproteomics-based molecular network description for high-resolution kinase-substrate interactome analysis. (2016)
  • Author(s): Narushima, Y., Kozuka-Hata, H., Tsumoto, K., Inoue, J. and Oyama, M.
  • Journal Title: Bioinformatics Volume: 印刷中 Issue: 14 Pages: 2083-2088
  • DOI: 10.1093/bioinformatics/btw164
  • Peer Reviewed / Open Access
• [Journal Article] nteraction of tumor necrosis factor receptor-associated factor 6 (TRAF6) and Vav3 in the receptor activator of nuclear factor kB (RANK) signaling complex enhances osteoclastogenesis. (2016)
  • Author(s): Yu, J., Yun, H., Shin, B., Kim, Y., Park, E.S., Choi, S., Yu, J., Amarasekara, D.S., Kim, S., Inoue, J., Walsh, M.C., Choi, Y., Takami, M. and Rho, J.
  • Journal Title: J. Biol. Chem. Volume: 291(39) Issue: 39 Pages: 20643-20660
  • DOI: 10.1074/jbc.m116.728303
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity (2015)
  • Author(s): Sato, Y., Goto, E., Shibata, Y., Kubota, Y., Yamagata, A., Goto-Ito, S., Kubota, K., Inoue, J., Takekawa, M., Tokunaga, F. and Fukai, S
  • Journal Title: Nat. Struct. Mol. Biol Volume: 22 Pages: 222-229
  • Peer Reviewed
• [Journal Article] HIV-1 replicates in human osteoclasts and enhances their differentiation in vitro. (2015)
  • Author(s): Gohda, J., Ma, Y., Huang, Y., Zhang, Y., Gu, L., Han, Y., Li, T., Gao, G.F., Inoue, J., Iwamoto, A. and Ishida, T.
  • Journal Title: Retrovirology Volume: 12 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s12977-015-0139-7
  • Peer Reviewed / Open Access
• [Journal Article] Catalytic subunits of the phosphatase calcineurin interact with NF-B-inducing kinase (NIK) and attenuate NIK-dependent gene expression. (2015)
  • Author(s): Shinzawa. M., Konno, H., Qin, J., Akiyama, N., Miyauchi, M., Ohashi, H., Miyamoto-Sato, E., Yanagawa, H., Akiyama, T.* and Inoue, J.
  • Journal Title: Sci. Rep Volume: 5 Issue: 1 Pages: 10758-10758
  • DOI: 10.1038/srep10758
  • Peer Reviewed / Open Access
• [Journal Article] Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice (2015)
  • Author(s): Takao Seki, Mami Yamamoto, Yuu Taguchi, Maki Miyauchi, Noritaka Yamaguchi, Jin Gohda, Taishin Akiyama, Jun-ichiro Inoue
  • Journal Title: Journal of Biochemistry Volume: 158 Pages: 485-495
  • DOI: 10.1093/jb/mvv064
  • NAID: 40020683863
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling (2015)
  • Author(s): Varney, M.E., Niederkorn, M., Konno, H., Matsumura, T., Gohda, J., Yoshida, N., Akiyama, T., Christie, S., Fang, J., Miller, D., Jerez, A., Karsan, A., Maciejewski, J.P., Inoue, J. and Starczynowski, D.T
  • Journal Title: J. Exp. Med Volume: 212 Issue: 11 Pages: 1967-1985
  • DOI: 10.1084/jem.20141898
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hypergravity provokes a temporary reduction in CD4+CD8+ thymocyte number and a persistent decrease in medullary thymic epithelial cell frequency in mice. (2015)
  • Author(s): Tateishi R, Akiyama N, Miyauchi M, Yoshinaga R, Sasanuma H, Kudo T, Shimbo M, Shinohara M, Obata K, Inoue J, Shirakawa M, Shiba D, Asahara H, Yoshida N, Takahashi S, Morita H, Akiyama T
  • Journal Title: PLOS ONE Volume: 10 Issue: 10 Pages: 1-17
  • DOI: 10.1371/journal.pone.0141650
  • Peer Reviewed / Open Access
• [Journal Article] Tropomodulin 1 expression driven by NF-kB enhances breast cancer growth. (2015)
  • Author(s): Ito-Kureha, T., Koshikawa, N., Yamamoto, M., Semba, K., Yamaguchi, N., Yamamoto, T., Seiki, M. and Inoue, J.
  • Journal Title: Cancer Res Volume: 75 Issue: 1 Pages: 62-72
  • DOI: 10.1158/0008-5472.can-13-3455
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] HTLV-1 Tax Induces K63-and M1-linked Hybrid Polyubiquitin Chains to Activate the IKK Complex (2017)
  • Author(s): Yuri Shibata, Ginga Komatsu, Jun-ichiro Inoue
  • Organizer: 18th International Conference on Human Retrovirology HTLV & Related Viruses
  • Place of Presentation: グランドアーク半蔵門
  • Year and Date: 2017-03-07
• [Presentation] ヒトT細胞白血病ウイルスの発癌タンパクの発癌タンパク質TaxによるNF-κB活性化機構 (2017)
  • Author(s): 井上純一郎
  • Organizer: 金沢大学がん進展制御研究所共同利用・共同研究拠点シンポジウム
  • Place of Presentation: 金沢東急ホテル
  • Year and Date: 2017-02-14
  • Invited
• [Presentation] TRAF6は乳腺上皮細胞の維持および乳腺上皮細胞の細胞死抑制によって妊娠期の乳腺発達を促進する (2017)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 先端モデル動物支援プラットフォーム
  • Place of Presentation: 琵琶湖ホテル
  • Year and Date: 2017-02-06
• [Presentation] 高深度天領リン酸化プロテオミクスと大規模インタラクトーム情報を基盤とする膠芽腫幹細胞情報伝達系の統合ネットワーク解析 (2016)
  • Author(s): 秦（小塚）裕子、成島悠太、廣木朋子、那須亮、津本浩平、井上純一郎、秋山徹、尾山大明
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] TRAF6は乳腺上皮細胞の維持および乳腺上皮細胞の細胞死抑制によって妊娠期の乳腺発達を促進する (2016)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Basal-like乳がんモデルマウスにおけるCRISPR/Cas9システムを利用したガン抑制遺伝子の探索 (2016)
  • Author(s): 坂根康太、山本瑞生、井上純一郎
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] ポリユビキチン鎖を介したHTLV-1 Tax誘導性のIKK複合体活性化機構の解析 (2016)
  • Author(s): 柴田佑里、井上純一郎
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] 乳腺発達と乳がん悪性化における転写因子NF-κBの役割の相違 (2016)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] 乳がんを標的とした新規NF-kappaB阻害剤の探索 (2016)
  • Author(s): 真鍋英里香、上松篤史、城戸康希、竹田浩之、高橋宏隆、山本瑞生、井上純一郎、澤崎達也
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] TRAF6は乳腺上皮細胞の維持および乳腺上皮細胞の細胞死抑制によって妊娠期の乳腺発達を促進する (2016)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 先端モデル動物支援 若手技術講習会
  • Place of Presentation: 蓼科グランドホテル滝の湯
  • Year and Date: 2016-09-14
• [Presentation] HTLV-1 Tax誘導性のIKK複合体活性化機構の解析 (2016)
  • Author(s): 井上純一郎 柴田佑里
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県市町村自治会館
  • Year and Date: 2016-08-26
• [Presentation] Analysis of HTLV-1 Tax-induced IKK activation pathway (2016)
  • Author(s): 柴田佑里、井上純一郎
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Whistler Conference Centre（カナダ バンクーバー）
  • Year and Date: 2016-03-13
  • Int'l Joint Research
• [Presentation] .Visualization of RelB expression and activation at the single-cell level during dendritic cell maturation in Relb-Venus knock-in mice (2016)
  • Author(s): 関崇生、山本真実、田口祐、宮内真紀、秋山伸子、山口憲孝、合田仁、秋山泰身、井上純一郎
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Whistler Conference Centre（カナダ バンクーバー）
  • Year and Date: 2016-03-13
  • Int'l Joint Research
• [Presentation] TRAF6 regulates pregnancy-induced mammary gland development and maintenance of epithelial stem cells (2016)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: Keystone symposia Stem Cells and Cancer (C1)
  • Place of Presentation: Beaver Run Resort（米国 コロラド州）
  • Year and Date: 2016-03-06
  • Int'l Joint Research
• [Presentation] Stimulation-dependent internalization of RANK is crucial for differentiation of osteoclast involved in bone metastasis (2016)
  • Author(s): 田口祐、井上純一郎
  • Organizer: Breakthroughs in Cancer Research:from Biology to Therapeutics
  • Place of Presentation: Hyatt Regency Maui（米国 ハワイ州）
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] 妊娠期の乳癌成熟および幹細胞維持におけるTRAF6の役割 (2015)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 第38回日本分子生物学会年会・第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] 転写因子NF-κBの制御メカニズムとその生理機能 (2015)
  • Author(s): 井上純一郎
  • Organizer: 数理医学研究会 第51回数理医学セミナー
  • Place of Presentation: 大阪大学（大阪府豊中市）
  • Year and Date: 2015-11-25
  • Invited
• [Presentation] 乳癌における細胞間相互作用による上皮感葉転換の制御 (2015)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際センター（愛知県名古屋市）
  • Year and Date: 2015-11-11
• [Presentation] Regulation of the TRAF-NF-κB and the Calcineurin-NFATc1 pathways in RANK signal-induced osteoclastogenesis (2015)
  • Author(s): 井上純一郎
  • Organizer: East Asia joint symposium
  • Place of Presentation: Oist Campus（沖縄県国頭郡）
  • Year and Date: 2015-11-11
  • Int'l Joint Research
• [Presentation] HTLV-1Tax誘導性のIKK複合体活性化におけるポリユビキチン鎖の機能解析 (2015)
  • Author(s): 柴田佑里、井上純一郎
  • Organizer: 日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所（東京都港区）
  • Year and Date: 2015-08-22
• [Presentation] 刺激依存的な受容体RANKの細胞質内局在化が果たす破骨細胞分化における役割 (2015)
  • Author(s): 田口祐、井上純一郎
  • Organizer: 日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-23
• [Presentation] 破骨細胞の分化成熟におけるTRAF6の役割 (2015)
  • Author(s): 弓桁洋、田口祐、井上純一郎
  • Organizer: 日本骨代謝学会学術集会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-07-23
• [Presentation] NF-κBシグナルによるTriple negative乳がんの悪性化 (2015)
  • Author(s): 井上 純一郎
  • Organizer: 癌研究分野の特性等を踏まえた支援活動 公開シンポジウム
  • Place of Presentation: 一橋講堂（東京都千代田区）
  • Year and Date: 2015-01-27 – 2015-01-28
  • Invited
• [Presentation] Tropomodulin 1 expression driven by NF-kB enhances breast cancer growth (2014)
  • Author(s): 井上 純一郎
  • Organizer: The 4th Japan-France Cancer Workshop
  • Place of Presentation: 関西セミナーハウス（京都府京都市）
  • Year and Date: 2014-11-19 – 2014-11-21
  • Invited
• [Presentation] Acceleration of carcinogenic spiral by dysregulated signal transduction (2014)
  • Author(s): 畠山昌則
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] 東京大学医科学研究所 分子発癌分野ホームページ
  • URL: https://www.traf6.com/