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Development of Notch4-targeted therapy for patients with HR-negative and HER2-negative breast cancer

Research Project

Project/Area Number 25461983
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General surgery
Research InstitutionKyushu University

Principal Investigator

KUBO Makoto  九州大学, 大学病院, 助教 (60403961)

Co-Investigator(Kenkyū-buntansha) KATANO Mitsuo  福岡女学院看護大学, 看護学部, 学長 (10145203)
NAKANO Kenji  九州大学, 先端融合医療レドックスナビ研究拠点, 教授 (00315061)
ONISHI Hideya  九州大学, 医学研究院, 准教授 (30553276)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsトリプルネガティブ乳癌 / Notchシグナル経路 / Notch4 / Stemness / Basal-like / BRCAness / Notch経路 / 浸潤性乳菅癌 / BRCA1ness
Outline of Final Research Achievements

This study shows that NOTCH4 receptor is a potential new therapeutic target for TNBC. First, NOTCH4 inhibition reduced proliferation and invasiveness in TNBC cells and reduced tumour volume and tumourigenicity, in vivo. Second, CD24 siRNA-transfected breast cancer cells (BCCs) demonstrated higher expression of Hedgehog signaling molecule, increased anchorage-independent proliferation, and enhanced invasiveness and superior tumorigenicity. DNA microarray analysis identified STAT1 as a relationship between CD24 and SHH. CD24 siRNA-transfected BCCs with concurrent STAT1 inhibition exhibited decreased SHH expression. Finally, we focused on instability of TNBC. Of the 71 TNBCs, 59 tumors (83%) were the basal-like phenotype. The results of the MLPA assays showed that 37 (62.7%) tumors had a BRCAness. Our study proved that TNBCs involve the stemness which activates Notch signaling and the BRCAness which increases gene instability.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (9 results)

All 2016 2015 2014 2013

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Acknowledgement Compliant: 1 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results)

  • [Journal Article] CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells.2016

    • Author(s)
      Suyama K, Onishi H, Imaizumi A, Shinkai K, Umebayashi M, Kubo M, Mizuuchi Y, Oda Y, Tanaka M, Nakamura M, Katano M.
    • Journal Title

      Cancer Letters

      Volume: 374(1) Issue: 1 Pages: 44-53

    • DOI

      10.1016/j.canlet.2015.12.013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] NOTCH4 is a potential therapeutic target for triple-negative breast cancer.2014

    • Author(s)
      Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M.
    • Journal Title

      Anticancer Res.

      Volume: 34(1) Pages: 69-80

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] TNBC-correlation with other markers to predict outcome2016

    • Author(s)
      Makoto Kubo
    • Organizer
      The 14th Asian Breast Diseases Association Meeting & Symposium
    • Place of Presentation
      スカラエスパシオ(福岡県・福岡市)
    • Year and Date
      2016-09-03
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Hh経路制御による乳癌幹細胞制御療法の開発2016

    • Author(s)
      巣山 久実、大西 秀哉、今泉 晃、片野 光男
    • Organizer
      第116回 日本外科学会定期学術集会
    • Place of Presentation
      大阪国際会議場(大阪府・大阪市)
    • Year and Date
      2016-04-15
    • Related Report
      2015 Annual Research Report
  • [Presentation] BRCAness and PD-L1 expression of Basal-like and Non-Basal-like Triple Negative Breast Cancer2015

    • Author(s)
      Hitomi Mori, Makoto Kubo, Mai Yamada, Masaya Kai, Masayuki Okido, Tomofumi Osako, Reiki Nishimura, Nobuyuki Arima, Yoshinao Oda, Masafumi Nakamura
    • Organizer
      The 38th San Antonio Breast Cancer Symposium (2015)
    • Place of Presentation
      Henry B. Gonzalez Convention Center・サンアントニオ(米国)
    • Year and Date
      2015-12-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 乳癌におけるCD24分子発現の意義:CD24分子発現とHh経路活性化の連関解析2015

    • Author(s)
      巣山 久実、大西 秀哉、今泉 晃、新海 健太郎、甲斐 昌也、田中 晴生、久保 真、田中 雅夫、片野 光男
    • Organizer
      第115回 日本外科学会定期学術集会
    • Place of Presentation
      名古屋国際会議場(愛知県・名古屋市)
    • Year and Date
      2015-04-16
    • Related Report
      2015 Annual Research Report
  • [Presentation] Hh経路制御による乳癌幹細胞制御療法の開発:CD24分子発現とHh経路活性化の連関解析2014

    • Author(s)
      巣山久実、大西秀哉、甲斐昌也、田中晴生、久保真、新海健太郎、永松伊織、松下章次郎、森藤良浩、今泉晃、田中雅夫、片野光男
    • Organizer
      第114回日本外科学会定期学術集会
    • Place of Presentation
      国立京都国際会館(京都府・京都市)
    • Year and Date
      2014-04-04
    • Related Report
      2014 Research-status Report
  • [Presentation] 乳癌細胞におけるCD24分子発現とHh経路活性化の連関の解析2013

    • Author(s)
      巣山 久実、大西 秀哉、甲斐 昌也、田中 晴生、久保 真、永松 伊織、今泉 晃、田中 雅夫、片野 光男
    • Organizer
      第26回日本バイオセラピィ学会学術集会
    • Place of Presentation
      いわて県民情報交流センターアイーナ(盛岡市)
    • Related Report
      2013 Research-status Report
  • [Presentation] トリプルネガティブ乳癌に対する新たな治療標的の同定:Notchシグナル系2013

    • Author(s)
      永松 伊織、甲斐 昌也、松下 章次郎、大西 秀哉、久保 真、中野 賢二、田中 雅夫、片野 光男
    • Organizer
      第26回日本バイオセラピィ学会学術集会
    • Place of Presentation
      いわて県民情報交流センターアイーナ(盛岡市)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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