A functional analysis of NFkB downregulation due to BRCA1 inhibition

• Project/Area Number: 16K19905
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Sakura Anna 聖マリアンナ医科大学, 医学研究科, 研究技術員 (80626698)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 乳癌 / BRCA1 / NfkBシグナリング / Bortezomib / 卵巣癌 / 分子標的治療 / NF-kBシグナリング / 癌

Outline of Final Research Achievements

Basal-like breast cancer, a subtype of breast cancer is associated with BRCA1 dysfunction. Basal-like breast cancer is linked to poorer clinical outcome, therefore effective treatment options for this subtype is desired. Recent reports have revealed that NFkB signaling is upregulated in breast cancer with BRCA1 mutation. We hypothesized that basal-like breast cancer with BRCA1 dysfunction could be sensitive to Bortezomib, a NFkB inhibitor.
Indeed, we have revealed that cancer cell lines with BRCA1 dysfunction due to both mutation and reduced expression displayed NFkB upregulation. Also, cells with BRCA1 dysfunction are sensitive to Bortezomib through NFkB inhibition. The last series of experiments using clinical samples showed reproducible results, suggesting that Bortezomib could be a reasonable therapeutic option for basal-like breast cancer with BRCA1 dysfunction. We have been preparing a manuscript to preset our data as a scientific paper.

Academic Significance and Societal Importance of the Research Achievements

Basal-like乳癌は予後不良と関連があり効果的治療方法の確立が重要である。効果的治療方法は、腫瘍だけに効果があること（選択性）と、安全性の確立された既存の薬剤で実現することが望ましい。本研究の結果により、BRCA1機能不全細胞ではNFkB経路がoncogene addictionを起こしていることを証明した。これはNFkB阻害薬がBRCA1機能不全細胞を選択的に死滅させるということである。そして本研究で用いたBortezomibは多発性骨髄腫の治療ですでに用いられている安全性の確立された薬剤である。これらの点で実用性に富んでいると考えられる。

Research Products

• [Int'l Joint Research] CNIC(スペイン)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] University of Cambridge(英国)
• [Int'l Joint Research] CNIC(Spain)
• [Int'l Joint Research] National University of Singapore(Singapore)
• [Int'l Joint Research] University of Cambridge(英国)
• [Int'l Joint Research] CINIC(Spain)
• [Int'l Joint Research] National University of Singapore(Singapore)
• [Journal Article] NF-kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol. (2020)
  • Author(s): Oda-Kawashima K1,2, Sedukhina AS1, Okamoto N1, Lytvyn M, Minagawa K, Iwata T, Kumai T, Sato E, Inada E, Yamaura A, Sakamoto M, Roche-Molina M, Bernal JA, Sato K
  • Journal Title: FEBS Open Bio Volume: 10 Issue: 2 Pages: 259-267
  • DOI: 10.1002/2211-5463.12783
  • Peer Reviewed / Open Access
• [Journal Article] EPO Signaling as a Predictive Marker of Disease Severity in RSV Infection (2017)
  • Author(s): Ayano Shinagawa, Kimino Minagawa, Hidekazu Yoshie, Tomoko Tsuruga, Keiko Oda, Hitoshi Yamamoto, Toshio Kumai, Juan A. Bernal, Ko Sato, Anna S. Sedukhina
  • Journal Title: International Journal of Innovative Research in Medical Science Volume: 2 Pages: 2455-8737
  • Peer Reviewed / Open Access
• [Journal Article] A Subclassification of Basal-like Breast Cancer for Prognostic Prediction (2017)
  • Author(s): Tomoko Tsuruga, Keiko Oda, Hidekazu Yoshie, Ayano Shinagawa, Kimino Minagawa, Toshio Kumai, Ko Sato, Anna S Sedukhina
  • Journal Title: International Journal of Innovative Research in Medical Science Volume: 2 Pages: 1031-1036
  • Peer Reviewed / Open Access
• [Journal Article] A bioinformatics-to-clinic sequential approach to analysis of prostate cancer biomarkers using TCGA datasets and clinical samples: a new method for precision oncology? (2017)
  • Author(s): Hidekazu Yoshie, Anna S. Sedukhina, Kimino Minagawa, Keiko Oda, Shigeko Ohnuma,Nobuyuki Yanagisawa, Ichiro Maeda, Masayuki Takagi, Hiroya Kudo, Ryuto Nakazawa, Hideo Sasaki,Toshio Kumai, Tatsuya Chikaraishi, and Ko Sato
  • Journal Title: Oncotarget Volume: 8 Issue: 59 Pages: 99601-99611
  • DOI: 10.18632/oncotarget.20448
  • Peer Reviewed / Open Access
• [Presentation] 前立腺癌におけるGRB2発現の生存期間と治療方法への影響 (2019)
  • Author(s): セドキーナアンナ 佐藤工
  • Organizer: 第78回日本癌学会学術総会(国際学会)
  • Int'l Joint Research
• [Presentation] トリプルネガティブ乳癌をモデルにしたプレシジョンオンコロジーのための多段階in silico解析 (2017)
  • Author(s): セドキーナアンナ
  • Organizer: 日本癌学会
• [Presentation] 合成致死を多くの予後不良癌へ (2016)
  • Author(s): セドキーナアンナ 佐藤工
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
  • Int'l Joint Research