Elucidation of extracellular matrix stiffness-dependent cell proliferation signaling pathways in breast cancer subtypes.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15503
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Osaka University
• Principal Investigator: Ichikawa Ayaka 大阪大学, 蛋白質研究所, 助教 (70869106)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 乳がん / がん微小環境 / 転写制御 / 細胞増殖 / ErbBシグナル伝達系

Outline of Final Research Achievements

This research project focused on the ErbB2 receptor signaling, which has been implicated in extracellular matrix stiffness, malignant transformation and breast cancer subtype classification, to determine the underlying molecular mechanisms from transcriptional regulation to cell cycle entry, and their impact on sensitivity to cell cycle inhibitors. The analysis of live cell imaging data using cell cycle reporters, combined with epigenetic and transcriptomic omics analysis, was validated using breast cancer cell lines with different levels of ErbB2 overexpression. The differential expression of ErbB2 was found to regulate the G1/S transition-associated c-Myc and cyclin D1 protein ratio. In addition, we identified one of the mechanisms by which how does ErbB2-mediated change in the ratio of c-Myc and cyclin D1 alter sensitivity to CDK4 inhibitors.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

ErbB2の発現量が比較的低いLuminal Aサブタイプ内において、局所的に観察されるErbB2の発現量の違いがどのように細胞周期制御の分子機構を調節するのか、その詳細なメカニズムは不明であった。本研究課題では、ErbB2、c-Myc、cyclin D1の発現量の比率の関係が、細胞周期の進行を制御し、細胞周期阻害剤処理後の増殖率を判定する上で重要な指標となる可能性を示した。また、乳がん細胞における細胞外マトリックス(ECM)の硬化は、ErbB2の発現量の変化と繋がっているため、今後、ECMの硬化具合がどのように細胞周期状態に影響し、薬剤応答性を変化させるのか、その予測に役立てることができる。