Genome-wide identification of double-strand break sites induced by activated estrogen receptors and Topoisomerase IIBeta

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22561
• 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: Kyoto University
• Principal Investigator: Takeda Shunichi 京都大学, 医学研究科, 教授 (60188191)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: BRCA1 / HBOC症候群 / 乳がん / 卵巣がん / DNA Topoisomerase IIB / エストロゲン / エンハンサー

Outline of Final Research Achievements

BRCA2 is a key player in homologous DNA recombination (HR), repairing double-strand breaks (DSBs) only at S/G2 in all cycling cells. It is unclear why loss of BRCA2 leads to an increase in carcinogenesis only in the mammary gland and ovary in HBOC syndrome. Our working hypothesis is that (i) TOP2 generates DSBs at E2-dependent enhancers during treatment with E2, (ii) BRCA2 play a crucial role in repairing TOP2-dependent DSBs independent of its function in HR, (iii) unrepaired breakage dysregulates transcriptional response to E2 in many genes, (iv) resulting overexpression of c-Myc oncogene in response to E2 explains oncogenesis in estrogen-regulated tissues, which explains the tissue specificity of HBOC. We have shown that (ii), (iii), and (iv) hypotheses are correct by analyzing the repair of TOP2-dependent DSBs in BRCA2-depleted G1 cells, transcriptome during response to E2, and c-Myc expression in BRCA2-deficient mice in cooperation with the Netherland Cancer Center, respectively.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

乳がんは、日本も含め東アジア全体で患者数が増加している。乳癌の問題点は、若い患者が多いことにある。BRCA1やBRCA2の変異のキャリアは乳癌の発症率が増加する（HBOC症候群）。BRCA1やBRCA2は、腫瘍抑制遺伝子であるにもかかわらず、なぜキャリアで発癌率が増加するのか不明である。この増加の原因は、キャリアの乳腺上皮がごくまれにloss of heterozygosityが起こるや否や、BRCA1やBRCA2の欠損によって一気に癌化が進む為と推定されている。この「一気に癌化が進む」分子機構が解明できれば、HBOC症候群の予防法開発と治療法開発に貢献できる。