Research on the breast cancer chemotherapy targeting synthetic lethality caused by the factors in the DNA damage repair pathways.

• Project/Area Number: 23300358
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor diagnosis
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: OHTA Tomohiko 聖マリアンナ医科大学, 医学(系)研究科(研究院), 教授 (60233136)
• Co-Investigator(Kenkyū-buntansha): BOKU Narikazu 聖マリアンナ医科大学, 医学部, 教授 (50505948) ; TSUGAWA Koichiro 聖マリアンナ医科大学, 医学部, 教授 (60313657) ; NAKADA Shinichiro 大阪大学, 医学(系)研究科(研究院), 准教授 (70548528)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥21,970,000 (Direct Cost: ¥16,900,000、Indirect Cost: ¥5,070,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2012: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: DNA修復 / 合成致死性 / 癌化学療法 / 乳癌 / 非癌遺伝子依存性

Research Abstract

In this project we studied the DNA damage repair pathways to employ the synthetic lethality caused by the factors in the pathway for breast cancer therapy. We found that promoter methylation of genes implicating in the homology-directed DNA repair are associated with chemosensitivity. We also discovered that overexpression of PLK1 causes cellular hypersensitivity to CPT-11 and PARP inhibitor through suppression of the E3 ubiquitin ligase activity of BRCA1, and that BARD1 interacts with Lys9-dimethylated Histone H3 through heterochromatin protein 1 (HP1) gamma in response to DNA damage.

Research Products

• [Journal Article] Fine-tuning of DNA damage-dependent ubiquitination by OTUB2 supports the DNA repair pathway choice (2014)
  • Author(s): Kato K, Nakajima K, Ui A, Muto-Terao Y, Ogiwara H, Nakada S
  • Journal Title: Mol Cell Volume: 53(4) Issue: 4 Pages: 617-30
  • DOI: 10.1016/j.molcel.2014.01.030
  • Peer Reviewed
• [Journal Article] Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy (2013)
  • Author(s): Watanabe Y, Maeda I, Oikawa R, Wu W, Tsuchiya K, Miyoshi Y, Itoh F, Tsugawa K, Ohta T
  • Journal Title: Genes to Cells Volume: 18(12) Issue: 12 Pages: 1120-1130
  • DOI: 10.1111/gtc.12100
  • Peer Reviewed
• [Journal Article] Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum : WJOG 4007 trial (2013)
  • Author(s): Hironaka S, Ueda S, Yasui H, Nishina T, Tsuda M, Tsumura T, Sugimoto N, Shimodaira H, Tokunaga S, Moriwaki T, Esaki T, Nagase M, Fujitani K, Yamaguchi K, Ura T, Hamamoto Y, Morita S, Okamoto I, Boku N, Hyodo I
  • Journal Title: J Clin Oncol Volume: 31(35) Issue: 35 Pages: 4438-44
  • DOI: 10.1200/jco.2012.48.5805
  • Peer Reviewed
• [Journal Article] RNF8 regulates assembly of RAD51 at DNA double-strand breaks in the absence of BRCA1 and 53BP1 (2012)
  • Author(s): Nakada S, Yonamine RM, Matsuo K
  • Journal Title: Cancer Res Volume: 72(19) Issue: 19 Pages: 4974-83
  • DOI: 10.1158/0008-5472.can-12-1057
  • Peer Reviewed
• [Journal Article] A DNA-Damage Selective Role for BRCA1 E3 Ligase in Claspin Ubiquitylation, CHK1 Activation, and DNA Repair (2012)
  • Author(s): Sato K, Sundaramoorthy E, Rajendra E, Hattori H, Jeyasekharan AD, Ayoub N, Schiess R, Aebersold R, Nishikawa H, Sedukhina AS, Wada H, Ohta T, Venkitaraman AR
  • Journal Title: Curr Biol Volume: 22 Issue: 18 Pages: 1659-66
  • DOI: 10.1016/j.cub.2012.07.034
  • Peer Reviewed
• [Journal Article] 乳癌治療におけるユビキチン修飾 (2012)
  • Author(s): 佐藤 工, 太田 智彦
  • Journal Title: 医学のあゆみ Volume: 243(6) Pages: 520-524
  • Peer Reviewed
• [Journal Article] 乳癌-基礎と臨床の最新研究動向-」III乳癌の分子生物学と発癌機序1. 分子生物学 (2)癌遺伝子と癌抑制遺伝子 (2012)
  • Author(s): 福田 貴代, セドキーナ アンナ, 太田智彦
  • Journal Title: 日本臨牀 : 増刊号「乳癌」 Volume: 9 Pages: 66-70
  • Peer Reviewed
• [Journal Article] BRCA1とDNA損傷応答 (2012)
  • Author(s): セドキーナ アンナ, 福田 貴代, 太田智彦
  • Journal Title: 生化学 Volume: 84(7) Pages: 637-640
  • NAID: 10030966547
  • Peer Reviewed
• [Journal Article] DNA 相同組換え修復と乳癌 (2012)
  • Author(s): 太田 智彦, 西川 裕之
  • Journal Title: Medical Science Digest Volume: 38(1) Pages: 637-40
  • Peer Reviewed
• [Journal Article] BRCA1とDNA損傷応答 (2012)
  • Author(s): セドキーナ・アンナ
  • Journal Title: 生化学 Volume: 84 Pages: 637-640
  • Peer Reviewed
• [Journal Article] 「乳癌―基礎と臨床の最新研究動向―」III 乳癌の分子生物学と発癌機序 1.分子生物学 （2）癌遺伝子と癌抑制遺伝子 (2012)
  • Author(s): 福田貴代
  • Journal Title: 日本臨牀 Volume: 9 Pages: 66-70
  • Peer Reviewed
• [Journal Article] 乳癌治療におけるユビキチン修飾 (2012)
  • Author(s): 佐藤工
  • Journal Title: 医学のあゆみ Volume: 243 Pages: 520-524
  • Peer Reviewed
• [Journal Article] DNA相同組換え修復と乳癌 (2012)
  • Author(s): 太田智彦
  • Journal Title: Medical Science Digest Volume: 38 Pages: 637-40
  • Peer Reviewed
• [Journal Article] HERC2 Interacts with Claspin and regulates DNA origin firingandr eplication fork progression (2011)
  • Author(s): Izawa N, Wu W, Sato K, Nishikawa H, Kato A, Boku N, Itoh F, Ohta T
  • Journal Title: Cancer Research Volume: Volume 71 Issue: 17 Pages: 5621-5625
  • DOI: 10.1158/0008-5472.can-11-0385
  • Peer Reviewed
• [Journal Article] The BRCA1 ubiquitin ligase and homologous recombination repair (2011)
  • Author(s): Ohta T
  • Journal Title: FEBS Lett Volume: 585 Issue: 18 Pages: 2836-44
  • DOI: 10.1016/j.febslet.2011.05.005
  • Peer Reviewed
• [Presentation] BRCA1-E3 inactivation leads to a failure of homologous recombination DNA repair in response to CPT-11 and PARPi (2013)
  • Author(s): 太田 智彦
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-10-03
• [Presentation] DNA損傷応答とBRCA1ユビキチンリガーゼ (2013)
  • Author(s): 太田 智彦
  • Organizer: 第86回日本生化学学会大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-09-12
• [Presentation] Homology-directed DNA repair competence as a possible biomarker for breast cancer chemosensitivity (2013)
  • Author(s): 太田 智彦
  • Organizer: 第11回日本臨床腫瘍学学会集会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2013-08-29
• [Presentation] DNA損傷応答におけるBRCA1,Claspinおよび HERC2の相互作用 (2013)
  • Author(s): 太田 智彦
  • Organizer: 第65回日本細胞生物学会大会
  • Place of Presentation: ウインクあいち(愛知県産業労働センター)
  • Year and Date: 2013-06-21
• [Presentation] Agent-specific cellular chemosensitivity attributed to loss of BRCA1 E3 ligase activity (2012)
  • Author(s): 太田 智彦
  • Organizer: 15th International Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: 石川県立音楽堂
  • Year and Date: 2012-11-15
• [Presentation] DNA replication and checkpoint regulated by HERC2 and BRCA1 E3 ubiquitin ligases (2012)
  • Author(s): 太田 智彦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: さっぽろ芸文館
  • Year and Date: 2012-09-19
• [Presentation] トリプルネガティブ乳癌に対する治療戦略 (2011)
  • Author(s): 太田 智彦
  • Organizer: 第19回日本乳癌学会学術集会
  • Place of Presentation: 仙台国際センター東北大学百周年記念会館
  • Year and Date: 2011-09-04
• [Presentation] トリプルネガティブ乳癌に対する治療戦略 (2011)
  • Author(s): 太田智彦
  • Organizer: 第19回日本乳癌学会学術集会プレジデンシャルシンポジウム
  • Place of Presentation: 仙台国際センター東北大学百周年記念会館(宮城県)
  • Year and Date: 2011-09-04
• [Presentation] DNA損傷応答におけるBRCA1, ClaspinおよびHERC2の相互作用
  • Author(s): 太田 智彦
  • Organizer: 第65回日本細胞生物学会大会
  • Place of Presentation: ウインクあいち（愛知県産業労働センター）
• [Presentation] Homology-directed DNA repair competence as a possible biomarker for breast cancer chemosensitivity
  • Author(s): 太田 智彦
  • Organizer: 第11回日本臨床腫瘍学会集会
  • Place of Presentation: 仙台国際センター
• [Presentation] DNA損傷応答とBRCA1ユビキチンリガーゼ
  • Author(s): 太田 智彦
  • Organizer: 第86回日本生化学学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] BRCA1-E3 inactivation leads to a failure of homologous recombination DNA repair in response to CPT-11 and PARPi
  • Author(s): 太田 智彦
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] DNA replication and checkpoint regulated by HERC2 and BRCA1 E3 ubiquitin ligases
  • Author(s): 太田 智彦
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: さっぽろ芸文館（北海道）
• [Presentation] Agent-specific cellular chemosensitivity attributed to loss of BRCA1 E3 ligase activity
  • Author(s): 太田 智彦
  • Organizer: 15th International Congress on Hormonal Steroids and Hormones & Cancer
  • Place of Presentation: 石川県立音楽堂（石川県）
• [Remarks] 聖マリアンナ医科大学大学院 医学研究科 応用分子腫瘍学
  • URL: http://www.marianna-u.ac.jp/t-oncology/index.html
• [Remarks] 聖マリアンナ医科大学大学院 医学研究科 応用分子腫瘍学
  • URL: http://www.marianna-u.ac.jp/t-oncology/index.html
• [Remarks]
  • URL: http://www.marianna-u.ac.jp/t-oncology/index.html