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Comprehensive analysis of mutant ERa found in cancers to reveal their aberrant functions

Research Project

Project/Area Number 19K07651
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionJapanese Foundation for Cancer Research

Principal Investigator

NAKADAI Tomoyoshi  公益財団法人がん研究会, がん研究所 がんエピゲノムプロジェクト, 研究員 (10364770)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsERa / Breast cancer / Mutation / FoxA1 / NcoA2 / ATAC-seq / ChIP-seq / K303R / 乳がん / ERα / 転写制御 / 変異体 / エストロゲン受容体α / 点変異体 / 転写制御異常 / ミスセンス変異体 / 内分泌療法 / 再構成転写系 / NGS / 1細胞RNA-seq / がん / 転写制御機構 / ミスセンス突然変異
Outline of Research at the Start

エストロゲン受容体ERαは、多様な分子機構により遺伝子の発現を制御するDNA結合型の転写活性化因子であり、乳がんを始めとする様々ながん腫において多様な突然変異の存在が報告されている。いくつかの変異はERα陽性乳がんに用いられる内分泌療法への耐性獲得機構の一端を担うと考えられているが、大部分の変異体における機能異常性の有無や、その異常化の分子機構は不明である。そこで当研究では、申請者の有する転写機構解析法である再構成転写系等の生化学解析法と、細胞生物学的手法を用いたスクリーニングを合わせて用いることにより、網羅的体系的に各変異体の機能異常性を分子レベルで明らかにし、病的意義の有無を明らかにする。

Outline of Final Research Achievements

MB453 inducibly expressing mutant K303R was established and ATAC/ChIP-seq analyses were performed. The results showed that both of wild type and the mutant K303R associated with DNA-bound FoxA1 indirectly, but only the mutant K303R opened those regions. Moreover, biochemical analyses showed that the mutant K303R induced the association of NcoA2 to FoxA1/DNA complex. These results proposed the novel mechanism of breast cancer development by the mutant K303R.
Nine ERa mutants, which were shown to exhibit functional abnormalities in the luciferase assay, were also introduced into MB453. ATAC/ChIP-seq analyses revealed that mutant A86V/S463P showed the constitutive active phenotype as Y537S, and also mutants E247K/E380Q showed the novel abnormality (induced association to AP-1 binding region).

Academic Significance and Societal Importance of the Research Achievements

これまで高頻度変異体ERαの解析によるがんの治療や診断への応用がすすんでいる。一方中程度以下の変異については、未解析かつがん化との関連性を統計学的に見出すことも難しい。本研究はこれらの問題点へ切り込むことを目的とし、ルシフェラーゼアッセイやNGS等の網羅的解析を行い、複数の変異体の異常性の有無と新規異常性について明らかにした。特に変異体K303Rの異常性の分子機構(NcoA2のFoxA1会合の促進)を解明、新規がん化機構の提唱を行った。同時に野生型ERαの間接的FoxA1への会合を発見、野生型ERaの新機能を発見した。以上、本研究はERaの新規機能とERα変異を有するがんの理解へつながった。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2021 2020 2019

All Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (5 results)

  • [Journal Article] Sumoylation of the human histone H4 tail inhibits p300-mediated transcription by RNA polymerase II in cellular extracts2021

    • Author(s)
      Calvin Jon A Leonen, Miho Shimada, Caroline E Weller, Tomoyoshi Nakadai, Peter L Hsu, Elizabeth L Tyson, Arpit Mishra, Patrick Mm Shelton, Martin Sadilek, R David Hawkins, Ning Zheng, Robert G Roeder, Champak Chatterjee
    • Journal Title

      eLife

      Volume: 8

    • DOI

      10.7554/elife.67952

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer2021

    • Author(s)
      Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, et. al.
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 35

    • DOI

      10.1073/pnas.2025647118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 癌で検出される多様な変異体ERαの網羅的解析と分子機能異常性の解明2021

    • Author(s)
      中太 智義、楊美麗、大塚裕美、粂川晃平、宮木里帆、丸山 玲緒
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 癌て検出される多様な変異体ERaの分子機能異常性の網羅的解析と病的意義の解明2021

    • Author(s)
      中太 智義、粂川晃平、丸山 玲緒
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Comprehensive analysis of mutant ERa detected in various cancers to reveal their aberrant molecular functions and pathological significances2020

    • Author(s)
      中太智義
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Comprehensive analysis of mutant ERa detected in various cancers to reveal their aberrant molecular functions and pathological significances2020

    • Author(s)
      中太智義
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 癌で検出される多様な変異体ERaの分子機能異常性の網羅的解析と病的意義の解明2019

    • Author(s)
      中太智義、楊麗英、丸山玲緒
    • Organizer
      日本分子生物学会第42回年会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2024-01-30  

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