Elucidation of homologous recombination depending on X-chromosome status which associates onset and progression of female tumors

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22559
• 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: Hamamatsu University School of Medicine
• Principal Investigator: Kitagawa Masatoshi 浜松医科大学, 医学部, 教授 (50294971)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: 相同組換え / X染色体

Outline of Final Research Achievements

In mammalian somatic cells, the unilateral X chromosome is inactivated (XaXi). On the other hand, in undifferentiated cells, both X chromosomes are in an activated state (XaXa). In this study, (1) male and female ES cells were established from the same parent mouse, and it was proved that females have lower homologous recombination repair ability (HR) than males. (2) Using female ES cells introduced with Dox-induced Xist, it was demonstrated that XaXi (Dox (+)) restores HR activity to the same extent as males. (3) It was proved that BRCC3, which is on the X chromosome and acts to suppress homologous recombination repair, is highly expressed in females and is involved in HR suppression. (4) It was found that the publication was launched for human breast cancer and the prognosis of patients.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果はヒトの女性乳がんにおけるin silico解析で、両X染色体の活性化を示唆するXistが低発現の患者の予後が不良で、両X染色体の活性化により発現亢進するBRCC3の高発現の患者の予後が不良であることが示唆された。このことは乳がんなどの女性腫瘍で両X染色体が活性化している場合は、BRCC3の発現が亢進することで相同組換え修復が低下し、変異の蓄積やゲノムの不安定性が高まり、悪性亢進の可能性が高まることが予想される。本研究成果は女性がん細胞においては、X染色体の活性化やBRCC3の発現を指標にした新たな予後予測が可能であることを示唆しており、さらに検証を進めていく予定である。