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Therapeutic advances in BIG3-PHB2 inhibition targeting the cross-talk between estrogen and growth factors in breast cancer

Research Project

Project/Area Number 26461948
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General surgery
Research InstitutionThe University of Tokushima

Principal Investigator

YOSHIMARU Tetsuro  徳島大学, 先端酵素学研究所(プロテオ), 講師 (80424729)

Co-Investigator(Renkei-kenkyūsha) KATAGIRI Toyomasa  徳島大学, 先端酵素学研究所, 教授 (60291895)
MIYOSHI Yasuo  兵庫医科大学, 医学部, 教授 (50283784)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords内分泌療法耐性乳癌 / エストロゲン受容体 / 乳癌 / クロストーク / 内分泌療法耐性乳がん / 乳がん / アロマターゼ阻害剤
Outline of Final Research Achievements

We demonstrated that specific inhibitor of the BIG3-PHB2 complex, which is a critical modulator in estrogen (E2) signaling, ERAP, leads to suppression of E2-dependent estrogen-signaling activation. Here, we report that ERAP has significant suppressive effects against synergistic activation caused by the cross-talk between E2 and growth factors associated with intrinsic or acquired resistance to endocrine-therapy in breast cancer cells. Importantly, combined treatment with ERAP and some known anti-estrogen led to a synergistic suppression of signaling that was activated by cross-talk between E2 and growth factors or HER2 amplification. Furthermore, BIG3 overexpression is strongly associated with poor prognosis of breast cancer.
Taken together, our findings suggest that the specific inhibition of BIG3-PHB2 is a novel potential therapeutic approach for the treatment of endocrine-resistant breast cancers activated by the cross-talk between E2 and growth factor signaling.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (21 results)

All 2017 2016 2015 2014

All Journal Article (11 results) (of which Peer Reviewed: 9 results,  Open Access: 9 results,  Acknowledgement Compliant: 6 results) Presentation (10 results) (of which Int'l Joint Research: 2 results)

  • [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
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [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
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor2017

    • Author(s)
      Y. Shikata Y, T. Yoshimaru, M. Komatsu, H. Katoh, R. Sato, S. Kanagaki, Y. Okazaki, S. Toyokuni, E. Tashiro, S. Ishikawa, T. Katagiri, M. Imoto,
    • Journal Title

      Cancer Science

      Volume: 108 Issue: 4 Pages: 785-794

    • DOI

      10.1111/cas.13175

    • NAID

      120006535004

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 包括的ゲノム解析を通じた乳癌の発症・進展機構解明の現状と展望2017

    • Author(s)
      松下洋輔、吉丸哲郎、片桐豊雅
    • Journal Title

      日本臨牀

      Volume: 75 Pages: 155-160

    • Related Report
      2016 Annual Research Report
  • [Journal Article] 包括的ゲノム解析を通じたトリプルネガティブ乳癌の分子特性2016

    • Author(s)
      吉丸哲郎、松下洋輔、片桐豊雅
    • Journal Title

      乳癌の臨床

      Volume: 31 Pages: 377-385

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer.2015

    • Author(s)
      Yoshimaru T, Komatsu M, Miyoshi Y, Honda J, Sasa M, Katagiri T
    • Journal Title

      Cancer Science

      Volume: 106 Issue: 5 Pages: 550-558

    • DOI

      10.1111/cas.12654

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] BIG3 inhibit the estrogen-dependent nuclear translocation of PHB2 via multiple Karyopherin-alpha proteins in breast cancer cells.2015

    • Author(s)
      Kim NH, Yoshimaru T, Chen YA, Matsuo T, Komatsu M, Miyoshi Y, Tanaka E, Sasa M, Katagiri T
    • Journal Title

      PLoS One

      Volume: 10 Issue: 6 Pages: e0127707-e0127707

    • DOI

      10.1371/journal.pone.0127707

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer2015

    • Author(s)
      Yoshimaru T, Komatsu M, Miyoshi Y, Honda J, Sasa M, Katagiri T
    • Journal Title

      Cancer Sci

      Volume: in press Pages: 12654-12654

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) is predicted to interact with its partner through an ARM-type α-helical structure2014

    • Author(s)
      Mizuguchi K., Chen Y. A., Murakami Y., Ahmad S., Yoshimaru T., Katagri T.
    • Journal Title

      BMC Res Notes

      Volume: 7 Issue: 1 Pages: 435-435

    • DOI

      10.1186/1756-0500-7-435

    • NAID

      120006864075

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Early growth response 4 is involved in cell proliferation of small cell lung cancer through transcriptional activation of its downstream genes2014

    • Author(s)
      Matsuo T, Dat le T, Komatsu M, Yoshimaru T, Daizumoto K, Sone S, Nishioka Y, Katagiri T
    • Journal Title

      PLoS One

      Volume: 9 Issue: 11 Pages: e113606-e113606

    • DOI

      10.1371/journal.pone.0113606

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Xanthohumol suppresses oestrogen-signalling in breast cancer through the specific inhibition of BIG3-PHB2 interaction.2014

    • Author(s)
      Yoshimaru T, Komatsu M, Tashiro E, Imoto M, Osada H, Miyoshi M, Honda J, Sasa M, and Katagiri T
    • Journal Title

      Scientific Report

      Volume: 4 Issue: 1 Pages: 7335-7335

    • DOI

      10.1038/srep07355

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] A novel A-kinase anchoring protein, BIG3, coordinates estrogen signalling in breast cancer cells2016

    • Author(s)
      Tetsuro Yoshimaru, Masaya Ono, Kenji Mizuguchi, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri
    • Organizer
      The 12th International Conference on Protein Phosphatase
    • Place of Presentation
      近畿大学 東大阪キャンパス 11月ホール(大阪府東大阪市)
    • Year and Date
      2016-11-27
    • 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 cancer2016

    • Author(s)
      Tetsuro Yoshimaru, Toyomasa Katagiri
    • Organizer
      2nd International Symposium on Molecular Medicine in Tokushima University
    • Place of Presentation
      徳島大学 大塚講堂(徳島県徳島市)
    • Year and Date
      2016-11-17
    • 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 cancer2016

    • Author(s)
      Tetsuro Yoshimaru, Yosuke Matsushita, Masato Komatsu, Yasumasa Okazaki, Shinya Toyokuni, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri
    • 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] 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
    • Place of Presentation
      別府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
  • [Presentation] BIG3-PHB2相互作用阻害ペプチドstERAPによる内分泌治療耐性乳がん治療薬の開発2016

    • Author(s)
      吉丸哲郎、片桐豊雅
    • Organizer
      平成27年度 革新的特色研究シンポジウム 徳大薬学部創薬シーズの整備と蔵本ネットワークを 基盤としたアカデミア創薬研究
    • Place of Presentation
      徳島大学薬学部 第一講義室(徳島県徳島市)
    • Year and Date
      2016-03-16
    • Related Report
      2015 Research-status Report
  • [Presentation] BIG3-PHB2 interaction is a key potential therapeutic target in luminal-type breast cancer2015

    • Author(s)
      Tetsuro Yoshimaru, Masato Komatsu, Etsu Tashiro, Hiroyuki Osada, Masaya Imoto, Shinya Toyokuni, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri
    • Organizer
      第74回日本癌学会・学術総会
    • Place of Presentation
      名古屋国際会議場(愛知県名古屋市)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がん治療法の創製2015

    • Author(s)
      吉丸哲郎、小松正人、田代 悦、長田裕之、井本正哉、片桐豊雅
    • Organizer
      第19回日本がん分子標的治療学会
    • Place of Presentation
      松山全日空ホテル(愛媛県松山市)
    • Year and Date
      2015-06-10
    • Related Report
      2015 Research-status Report
  • [Presentation] エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がん治療法の開発2015

    • Author(s)
      吉丸哲郎、小松正人、三好康雄、本田純子、笹 三徳、片桐豊雅
    • Organizer
      第72回徳島乳腺研究会
    • Place of Presentation
      徳島大学病院 日亜メディカルホール(徳島県徳島市)
    • Year and Date
      2015-04-25
    • Related Report
      2015 Research-status Report
  • [Presentation] New therapeutics for luminal-type breast cancer targeting BIG3-PHB2 interaction2014

    • Author(s)
      Tetsuro Yoshimaru, Masato Komatsu, Taisuke Matsuo, Yasuo Miyoshi, Mitsunori Sasa, Yusuke Nakamura, Toyomasa Katagiri
    • 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
    • Related Report
      2014 Research-status Report
  • [Presentation] エストロゲン受容体制御分子BIG3を標的とした新規ER陽性乳がん治療法の創製2014

    • Author(s)
      吉丸哲郎、小松正人、松尾泰祐、片桐豊雅
    • Organizer
      第18回日本がん分子標的治療学会
    • Place of Presentation
      TKPガーデンシティ仙台(宮城県仙台市)
    • Year and Date
      2014-06-25 – 2014-06-27
    • Related Report
      2014 Research-status Report

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Published: 2014-04-04   Modified: 2018-03-22  

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