The importance of NGLY1 on the chemoresistance of triple negative breast cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06092
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Fujihira Haruhiko 国立研究開発法人理化学研究所, 開拓研究本部, 研究員 (50721057)
• Co-Investigator(Kenkyū-buntansha): 堀本 義哉 順天堂大学, 医学部, 客員准教授 (40424246)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: NGLY1 / TNBC / 薬剤耐性

Outline of Final Research Achievements

In this study, we aimed to clarify the mechanism by which NGLY1 contributes to drug resistance in triple-negative breast cancer (TNBC) and found the followings: (1) TNBC cells with lower endogenous expression levels of NGLY1 tend to be more resistant to anticancer drugs (e.g. doxorubicin, docetaxel), (2) Knockdown (KD) of NGLY1 in TNBC cells increases anticancer drug resistance, (3) KD of NGLY1 in TNBC cells dysregulates cell cycle, (4) KD of NGLY1 in TNBC cells reduces the expression of genes that contribute to DNA repair, and (5) in clinical samples, patients who responded less well to chemotherapy had lower NGLY1 expression. Although we were unable to conduct the analysis using nude mice as originally planned, we developed an ELISA-based NGLY1 activity measurement system that can be used in clinical settings, which had not been anticipated.

Free Research Field

糖鎖生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、糖鎖脱離酵素NGLY1がトリプルネガティブ乳がん（TNBC）の薬剤耐性に寄与する可能性を示すことができた。これまでNGLY1の重要性に関してはNGLY1欠損症との関連が主に着目され、他の疾患（がん、心疾患など）との関連については研究が進んでいない。本研究の結果から、新たにTNBCとNGLY1との関連性という新たな学術的領域を見出すことができた。また、追加での検証が必要だが、NGLY1の発現量とTNBCの薬剤耐性との関連性が確実なものとなれば、患者のNGLY1発現量（活性）を測定することで、患者の薬剤耐性を予測することが可能となり、TNBC患者の予後の改善へ貢献することができる。