2023 Fiscal Year Final Research Report

Tissue-specific carcinogenesis due to dysregulation of centrosome duplication by BRCA1 complex

Research Project

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Project/Area Number	21K07143
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 50010:Tumor biology-related
Research Institution	Tohoku University
Principal Investigator	Yoshino Yuki 東北大学, 加齢医学研究所, 助教 (60755700)
Co-Investigator(Kenkyū-buntansha)	千葉奈津子東北大学, 加齢医学研究所, 教授 (50361192)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	BRCA1 / 中心体 / RACK1
Outline of Final Research Achievements	BRCA1 is one of the responsible genes for hereditary breast cancer. It has not been well understood why BRCA1 dysfunction causes carcinogenesis in tissue-specific manner. In this study, we investigated the molecular mechanism of centrosome regulation by the centrosomal BRCA1 complex. To elucidate the function of the centrosomal BRCA1 complex in centrosome regulation, we knocked down RACK1, a component of the centrosomal BRCA1 complex, and investigated abnormalities induced by that, In RACK1-knockdown cells, centrosome duplication was hampered at the very early stage of the duplication. We screened several mitotic kinases which involves centrosome regulation and found one kinase as a regulatory target of RACK1. In addition, we identified a novel interactant of RACK1 and found that the interactant regulated the stability of the kinase in protein level.
Free Research Field	腫瘍生物学
Academic Significance and Societal Importance of the Research Achievements	BRCA1変異キャリア患者では乳がん発症率が80%と高く、かつ若年発症例も多い。乳がん発症を予防するには、現時点では予防的に乳房を切除する他ないが、健常な乳房を切除することは美容的、心理的に侵襲が大きい。したがって、BRCA1変異キャリア患者における乳がんの発症を積極的に抑制する非外科的治療法の開発が望まれている。発がんを抑制するには、細胞ががん化する過程を理解し、がん化に必須のステップを標的とする薬剤を開発する必要がある。本研究はBRCA1複合体の機能障害による乳腺上皮細胞特異的ながん化メカニズムの一端を解明するものであり、将来のがん化抑制薬の開発の基盤的知識を提供するものと考えられる。