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Clarification of novel pathophysiological roles of BIG3 in breast cancer cells

Research Project

Project/Area Number 16H05153
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionThe University of Tokushima

Principal Investigator

KATAGIRI Toyomasa  徳島大学, 先端酵素学研究所(プロテオ), 教授 (60291895)

Research Collaborator YOSHIMARU Tetsuro  徳島大学, 先端酵素学研究所(プロテオ), 講師 (80424729)
MATSUSHITA Yosuke  徳島大学, 先端酵素学研究所(プロテオ), 助教 (70634450)
ONO Masaya  国立研究開発法人国立がん研究センター, 研究所, ユニット長 (00270900)
MUZUGUCHI Kenji  国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 バイオインフォマティクスプロジェクト, プロジェクトリーダー (50450896)
OTAKA Akira  徳島大学, 大学院医歯薬学研究部(薬学系), 教授 (20201973)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywordsbreast cancer / estrogen signaling / tumor suppressor / phosphorylation / dephosphorylation / oncogenic signaling / mitochondrial regulation / 癌 / ゲノム / 生体機能利用 / タンパク質 / プロテオーム
Outline of Final Research Achievements

We aimed to elucidate the pathophysiological functions of BIG3 that frequently up-regulated in breast cancers. In this study, we demonstrated the HER2-EGF signals-dependent phosphorylation sites for PHB2 inhibitory activity in HER2-positive breast cancer cells. Next, we generated the antibody which can specifically recognize each phosphorylation sites of PHB2 and demonstrated the specific cytoplasmic and mitochondrial localization of BIG3-PHB2 complex in HER2-positive breast cancer cells. Also, we observed mitochondrial morphological abnormalities caused by BIG3-PHB2 interaction inhibition, suggesting that BIG3-PHB2 plays an important role in maintaining mitochondrial morphology. Furthermore, we did optimization of BIG3-PHB2 interaction peptide inhibitor by intramolecular crosslinking methods, and succeed to improve its more antitumor effect.

Academic Significance and Societal Importance of the Research Achievements

乳がんでは、エストロゲン受容体(ER),プロゲステロン受容体(PgR)、HER2の三大受容体の発現に基づいた治療薬が主流であるが、これら受容体の活性化機序は多岐にわたり、その陽性率だけで治療方針の決定ができない症例も少なくない。その原因として、申請者らが同定したBIG3による抑制因子PHB2の制御がこれまで知られていなかったことがあげられる。本研究における、BIG3複合体によるPHB2の抑制活性の制御介した乳がん細胞増殖機序の解明は、現在のこれら三大受容体の発現に基づいた治療指針を大きく変える可能性があり、未だ不明な点が多い乳がん細胞の増殖機構に重要な知見を提供すると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (36 results)

All 2019 2018 2017 2016

All Journal Article (13 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 13 results,  Open Access: 13 results,  Acknowledgement Compliant: 5 results) Presentation (23 results) (of which Int'l Joint Research: 9 results,  Invited: 8 results)

  • [Journal Article] Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.2019

    • Author(s)
      Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.
    • Journal Title

      Nat Commun.

      Volume: 9 Issue: 1 Pages: 4083-4083

    • DOI

      10.1038/s41467-018-06581-8

    • NAID

      120006949472

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A DDX31/mutant-p53/EGFR axis promotes multistep progression of muscle invasive bladder cancer2018

    • Author(s)
      Daizumoto Kei、Yoshimaru Tetsuro、Matsushita Yosuke、Fukawa Tomoya、Uehara Hisaori、Ono Masaya、Komatsu Masato、Kanayama Hiro-omi、Katagiri Toyomasa
    • Journal Title

      Cancer Research

      Volume: - Issue: 9 Pages: 2528-2528

    • DOI

      10.1158/0008-5472.can-17-2528

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer2018

    • Author(s)
      Miyagawa Yoshimasa、Matsushita Yosuke、Suzuki Hiromu、Komatsu Masato、Yoshimaru Tetsuro、Kimura Ryuichiro、Yanai Ayako、Honda Junko、Tangoku Akira、Sasa Mitsunori、Miyoshi Yasuo、Katagiri Toyomasa
    • Journal Title

      International Journal of Oncology

      Volume: - Pages: 4301-4301

    • DOI

      10.3892/ijo.2018.4301

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients2018

    • Author(s)
      Giraudet A-L, Cassier AP, Iwao-Fukukawa C, Garin G, Badel J-N, Kryza D, Chabaud K, Gilles-Afchain L, Clapisson G, Desuzinges C, Sarrut D, Halty A, Italiano A, Mori M, Tsunoda T, Katagiri T, Nakamura Y, Alberti L, Cropet C, Baconnier S, Berge-Montamat S, Pérol D, Blay J-Y
    • Journal Title

      BMC Cancer

      Volume: 18 Issue: 1 Pages: 646-646

    • DOI

      10.1186/s12885-018-4544-x

    • NAID

      120006814096

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] alpha-particle therapy for synovial sarcoma in the mouse using an astatine-211-labeled antibpdy against fizzled homolog 10.2018

    • Author(s)
      Li HK, Sugyo A, Tsuji AB, Morokoshi Y, Minegishi K, Nagasu K, Kanda H, Harada Y, Nagayama S, Katagiri T, Nakamura Y, Higashi T, Hasegawa S.
    • Journal Title

      Cancer Sci.

      Volume: 109 Issue: 7 Pages: 2302-2309

    • DOI

      10.1111/cas.13636

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Critical Role of Estrogen Receptor Alpha O-Glycosylation by N-Acetylgalactosaminyltransferase 6 (GALNT6) in Its Nuclear Localization in Breast Cancer Cells.2018

    • Author(s)
      Deng, B., Tarhan, Y.E., Ueda, K., Ren, L., Katagiri, T., Park, J.H., and Nakamura, Y.
    • Journal Title

      Neoplasia

      Volume: 20 Issue: 10 Pages: 1038-1044

    • DOI

      10.1016/j.neo.2018.08.006

    • NAID

      120007027664

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A prospective study to examine the accuracies and efficacies of prediction systems for response to neoadjuvant chemotherapy for muscle invasive bladder cancer.2018

    • Author(s)
      Kato Y, Zembutsu H, Takata R, Matsuura T, Kato R, Kanehira M, Iwasaki K, Yamada N, Katagiri T, Sugai T, Fujioka T, Nakamura Y, Obara W.
    • Journal Title

      Oncol Lett.

      Volume: 16 Pages: 5775-5784

    • DOI

      10.3892/ol.2018.9330

    • NAID

      120007099372

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Tumor size and proliferative marker geminin rather than Ki67 expression levels significantly associated with maximum uptake of 18F-deoxyglucose levels on positron emission tomography for breast cancers2017

    • Author(s)
      Nishimukai Arisa、Inoue Natsuko、Kira Ayako、Takeda Masashi、Morimoto Koji、Araki Kazuhiro、Kitajima Kazuhiro、Watanabe Takahiro、Hirota Seiichi、Katagiri Toyomasa、Nakamori Shoji、Akazawa Kouhei、Miyoshi Yasuo
    • Journal Title

      PLOS ONE

      Volume: Vol.12, No.9 Issue: 9 Pages: e0184508-e0184508

    • DOI

      10.1371/journal.pone.0184508

    • NAID

      120006534983

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.2017

    • Author(s)
      Yoshimaru T, Ono M, Bando Y, Chen YA, Mizuguchi K, Shima H, Komatsu M, Imoto I, Izumi K, Honda J, Miyoshi Y, Sasa M, Katagiri T
    • Journal Title

      Nature Communications

      Volume: 印刷中 Issue: 1 Pages: 15427-15427

    • DOI

      10.1038/ncomms15427

    • NAID

      120006535065

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Stapled BIG3 helical peptide ERAP potentiates antitumour activity for breast cancer therapeutics.2017

    • Author(s)
      Yoshimaru T, Aihara K, Komatsu M, Matsushita Y, Okazaki Y, Toyokuni S, Honda J, Sasa M, Miyoshi Y, Otaka A, Katagiri T
    • Journal Title

      Scientific Reports

      Volume: 印刷中 Issue: 1 Pages: 1821-1821

    • DOI

      10.1038/s41598-017-01951-6

    • NAID

      120006535017

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Stapled BIG3 helical peptide ERAP extends potent antitumor activity for breast cancer therapeutics2017

    • Author(s)
      Yoshimaru T*, Aihara K, Komatsu M, Matsushita Y, Okazaki Y, Toyokuni S, Honda J, Sasa M, Miyoshi Y, Otaka A, Katagiri T*
    • Journal Title

      Scientific Reports

      Volume: 印刷中

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A-kinase anchoring protein BIG3 coordinates oestrogen signaling in breast cancer cells2017

    • Author(s)
      〇Yoshimaru T, Ono M, Bando Y, Chen YA, Mizuguchi K, Shima H, Komatsu M, Imoto I, Izumi K, Honda J, Miyoshi Y, Sasa M, Katagiri T*
    • Journal Title

      Nature Communications

      Volume: 印刷中

    • NAID

      120006535065

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers2017

    • Author(s)
      Iwamoto T*, Katagiri T, Niikura N, Miyoshi Y, Kochi M, Nogami T, Shien T, Motoki T, Taira N, Omori M, Tokuda Y, Fujiwara T, Doihara H, Gyorffy B, Matsuoka J
    • Journal Title

      Oncotarget

      Volume: 印刷中

    • NAID

      120006576956

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] Targeting RHBDL2-SLC1A5 axis to overcome chemoresistance and progression intriple negative breast cancer2019

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      International Society of Precision Cancer Medicine (ISPCM) Annual Meeting 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] DDX31 cooperates with mutant p53 and EGFR to promote the multistep progression of invasive bladder cancer2018

    • Author(s)
      Toyomasa Katagiri, Kei Daizumoto, Tetsuro Yoshimaru, Yosuke Matsushita, Tomoya Fukawa, Ono Masaya and Hiro-omi Kanayama
    • Organizer
      American Association For Cancer Research ANNUAL MEETING 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Overcoming trastuzumab resistance in HER2-overexpressing breast cancer by utilizing PHB2, a tumor suppressor of multiple resistance pathways2018

    • Author(s)
      Tetsuro Yoshimaru, Yosuke Matsushita, Sasa Mitsunori, Miyoshi Yasuo and Toyomasa Katagiri
    • Organizer
      American Association for Cancer Research ANNUAL MEETING 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Stapled BIG3 helical peptide ERAP potentiates anti-tumor activity for breast cancer therapeutics2018

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      Society of Precision Cancer Medicine Annual Meeting 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 乳がん細胞における小胞体-ゴルジ体間シャトルを通じたIRE1活性化機構の解明2018

    • Author(s)
      片桐 豊雅
    • Organizer
      第91会日本生化学会大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] BIG3-PKA-PP1Cα複合体による癌抑制因子PHB2不活性化を介したトラスツズマブ耐性乳癌増殖機構と新規治療法開発2018

    • Author(s)
      吉丸 哲郎, 松下 洋輔, 笹 三徳, 三好 康雄, 片桐 豊雅
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規Aキナーゼアンカータンパク質BIG3による抑制因子PHB2の制御はHER2乳癌細胞増殖に必須である2018

    • Author(s)
      吉丸 哲郎,松下 洋輔,片桐 豊雅
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Novel therapeutic strategy for breast cancer utilizing activation of tumor suppressor PHB22018

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      The 34th Radiation Biology Center Internationl Symposium
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Comprehensive molecular features of triple negative breast cancers2018

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      he 13th International Symposium of the Institute Network for Biomedical Sciences
    • Related Report
      2018 Annual Research Report
  • [Presentation] がん抑制因子活性化を利用して新規乳がん治療薬の開発2018

    • Author(s)
      片桐豊雅
    • Organizer
      KOBR研究会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Stapled BIG3 helical peptide ERAP potentiates anti-tumor activity for breast cancer therapeutics2018

    • Author(s)
      片桐豊雅
    • Organizer
      International Society of Precision Cancer Medicine Annual Meeting 2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of estrogen/ estrogen receptor signallings in breast cancer cells2017

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      11th International Symposium of The Institute Network ``Frontiers in Biomedical Sciences'',
    • Place of Presentation
      徳島大学 徳島県徳島市
    • Year and Date
      2017-01-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast tumor2017

    • Author(s)
      片桐豊雅
    • Organizer
      米国癌学会 American Association For Cancer Research ANNUAL MEETING 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 新たなホルモン依存性乳がん治療薬の開発を目指して2017

    • Author(s)
      片桐豊雅
    • Organizer
      第42回日本外科系連合学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ホルモン依存性乳がん治療の刷新を目指したがん抑制因子活性化による新規治療薬の開発2017

    • Author(s)
      片桐豊雅
    • Organizer
      第25回日本乳癌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Development of chemically modified peptide inhibitor ERAP targeting BIG3-PHB2 complex on hormone-resistant breast cancer,2016

    • Author(s)
      Tetsuro Yoshimaru and Toyomasa Katagiri
    • Organizer
      2nd International Symposium of Molecular Medicine in Tokushima University
    • Place of Presentation
      徳島大学 徳島県徳島市
    • Year and Date
      2016-11-17
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A novel A-kinase anchoring protein BIG3, coordinates estrogen signalling in breast cancer cells2016

    • Author(s)
      Tetsuro Yoshimaru, Ono Masaya, Mizuguchi Kenji, Miyoshi Yasuo, Mitsunori Sasa and Toyomasa Katagiri
    • Organizer
      The 12th International Conference on Protein Phosphatase
    • Place of Presentation
      近畿大学 大阪府東大阪市
    • Year and Date
      2016-10-27
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Development of stapled peptides targeting BIG3-PHB2 interaction in breast cancer cells2016

    • Author(s)
      粟飯原 圭佑, 吉丸 哲郎, 小松 正人, 重永 章, 片桐 豊雅, 大髙 章
    • Organizer
      第53回ペプチド討論会/日本ペプチド学会
    • Place of Presentation
      京都テルサ 京都府京都市
    • Year and Date
      2016-10-26
    • Related Report
      2016 Annual Research Report
  • [Presentation] BIG3-PHB2相互作用を標的とした前立腺がん治療法の開発の可能性2016

    • Author(s)
      瀧 亮祐, 吉丸 哲郎, 大豆本 圭, 松下 洋輔, 木村 竜一朗, 尾野 雅哉, 片桐 豊雅
    • Organizer
      第75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
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] Novel targeting therapeutic strategy for estrogen-dependent breast cancer2016

    • Author(s)
      片桐 豊雅
    • Organizer
      第75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
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] 内分泌療法耐性乳がんに対するBIG3-PHB2相互作用阻害ペプチドの開発2016

    • Author(s)
      吉丸 哲郎, 松下 洋輔, 小松 正人, 岡崎 泰昌, 豊國 伸哉, 笹 三徳, 三好 康雄, 片桐 豊雅
    • Organizer
      第75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
      2016-10-06
    • Related Report
      2016 Annual Research Report
  • [Presentation] 相互作用阻害によるがん抑制因子の再活性化を利用した難治性乳がんに対する新規治療薬の開発2016

    • Author(s)
      片桐 豊雅
    • Organizer
      構造活性フォーラム2016
    • Place of Presentation
      兵庫県立淡路夢舞台国際会議場 兵庫県淡路市
    • Year and Date
      2016-06-24
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] ホルモン療法耐性乳がん治療を目的とした分子内架橋型BIG3-PHB2相互作用阻害ペプチドの開発2016

    • Author(s)
      吉丸 哲郎, 小松 正人, 片桐 豊雅
    • Organizer
      第20回日本がん分子標的治療学会学術集会
    • Place of Presentation
      別府国際コンベンションセンター 大分県別府市
    • Year and Date
      2016-05-30
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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