RNA regulator in breast cancer stem cells and its application to therapy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19403
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Asahara Hiroshi 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (70294460)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: RNA binding protein / breast cancer / cancer stem cell

Outline of Final Research Achievements

The presence of cancer stem cells characterizes the treatment resistance of triple-negative breast cancer, a subtype of breast cancer known for its treatment resistance and low survival rate. We identified RBD24 as an RNA-binding protein specifically expressed in the breast cancer stem cell population, thereby characterizing its cancer stem cell properties at the post-transcriptional layer. RBD24 stabilizes target mRNAs by binding to cis-elements in the 3’UTR of various gene mRNAs, and contributes to tumorigenic potential and acquisition of drug resistance. We found ZEB1 as an upstream transcription factor that regulates RBD24 expression and serves as a target of RBD24, forming a positive feedback loop linking RNA layer and transcriptional layer. We showed that the RBD24-ZEB1 axis contributes to treatment resistance and tumorigenecity in vitro and in vivo.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

難治性で知られるトリプルネガティブ乳癌は抗癌剤に対して治療抵抗性を有し、有効な治療標的を持たないことから新規治療標的の探索が求められてきた。今回の研究成果はRBD24がトリプルネガティブ乳癌治療における新規治療標的となりうることを示唆するものである。また、RNA階層における癌の進展の制御の重要性を示しており、今後RNA階層を標的とした核酸医薬等による新規治療戦略の創出が期待される。