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Drug discovery in breast cancer utilizing reactivation of tumor suppressors

Research Project

Project/Area Number 17K19601
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Tumor biology and related fields
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) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Keywordsbreast cancer / drug discovery / multistep carcinogenesis / タンパク相互作用阻害 / tumor suppressor / 乳がん / ミトコンドリア / がん抑制因子 / がん特異的発現亢進因子 / HER2 / 創薬
Outline of Final Research Achievements

We aimed to propose the mechanism of the novel multistep carcinogenesis of breast cancer based on inactivation of tumor suppressor PHB2 via BIG3 complex that frequently up-regulated in breast cancers. In this study, we identified the several proteins which bind to BIG3 through the BIG3 antibody mediated-immunoprecipitation and mass spec analyses. Among them, several mitochondrial proteins were included. Moreover, we also identified the kinases which are responsible for PHB2 phosphorylations in breast cancer cells. Next, we did next-generation RNA sequencing on 15 triple negative breast cancer (TNBC) and exome seq on 30 TNBC cases and found some candidate tumor suppressor genes which had several somatic mutations in some cases. 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の抑制活性の制御を介した乳がん多段階発がんの分子機序の解明は、これまでの治療指針、特に、既存の乳がん治療薬耐性症例に対する治療を大きく変える重要な知見を提供すると考えられる。

Report

(2 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • Research Products

    (16 results)

All 2019 2018

All Journal Article (7 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 2 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
    • 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
    • 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
  • [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 Katagir
    • 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
      International 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
  • [Presentation] Comprehensive molecular features of triple negative breast cancers2018

    • Author(s)
      Toyomasa Katagiri
    • Organizer
      The 13th International Symposium of the Institute Network for Biomedical Sciences
    • Related Report
      2018 Annual Research Report

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Published: 2017-07-21   Modified: 2020-03-30  

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