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2018 Fiscal Year Final Research Report

Drug discovery in breast cancer utilizing reactivation of tumor suppressors

Research Project

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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
Keywordsbreast cancer / drug discovery / multistep carcinogenesis / タンパク相互作用阻害 / tumor suppressor
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.

Free Research Field

分子腫瘍学

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。

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Published: 2020-03-30  

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