A novel strategy by PARP inhibitors for sporadic breast cancers

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07686
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kindai University (2022-2023); Fujita Health University (2020-2021)
• Principal Investigator: Kuwahara Kazuhiko 近畿大学, 大学病院, 講師 (10263469)
• Co-Investigator(Kenkyū-buntansha): 酒井 康弘 浜松医科大学, 医学部, 准教授 (20754394)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 乳癌 / 転写共役型DNA傷害

Outline of Final Research Achievements

Inhibitors of poly (ADP-ribose) polymerase (PARP) have emerged as a new class of anti-cancer drugs, specifically for malignancies bearing aberrations of the homologous recombination pathway. They are clinically used in breast, ovarian, and pancreatic cancers. BRCA mutations are observed only in 5% among the patients with breast cancers; therefore, PARP inhibitors are ineffective to most of the patients with non-hereditary sporadic breast cancers. We found that PARP inhibitors could suppress the proliferation of breast cancer cells after ganp knockdown. In breast cancer cells, we demonstrate a novel strategy by PARP inhibitors through BRCAness induced by GANP-deficiency.

Free Research Field

実験病理

Academic Significance and Societal Importance of the Research Achievements

乳癌発症には女性ホルモンの長期暴露、欧米型の生活習慣などが危険因子となるが、95%を占める非遺伝性散発性乳癌ではその原因には不明な点が多い。家族性乳癌の原因遺伝子BRCA1とBRCA2の解析から両者がDNA修復に関与することが示され、乳癌が「DNA修復機構の異常による疾患」であることが明らかにされた。我々は転写共役型DNA傷害の制御に関わる分子GANPの機能不全と非遺伝性散発性乳癌発症に着目し、GANPの標的分子の一つがBRCA2であることを見出した。GANPを強制的に発現低下させることでBRCA2を抑制でき、PARP阻害剤の適応を非遺伝性散発性乳癌にまで拡げることが可能となる。