Development of novel therapeutic strategies for triple negative breast cancer

• Project/Area Number: 17K18336
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology; Tumor therapeutics
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Maruyama Reo 公益財団法人がん研究会, がん研究所 がんエピゲノムプロジェクト, プロジェクトリーダー (60607985)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 乳がん / エピゲノム / 乳癌 / 多様性 / 腫瘍生物学

Outline of Final Research Achievements

In this study, we aim to dissect the epigenetic heterogeneity and the gene regulatory landscape in BC cells by utilizing ATAC-seq method. We first obtained ATAC-seq profiles of 26 BC cell lines. We observed that ER+ and/or HER2+ BC cells show homogeneous patterns, whereas TNBC cells display a high degree of heterogeneity. To explore the epigenetic heterogeneity in TNBC cells in more detail, we performed motif analysis of distal regulatory elements in each cell line. We finally identified several key TFs that potentially contribute to the epigenetic heterogeneity in TNBC cells.

Academic Significance and Societal Importance of the Research Achievements

トリプルネガティブ乳がん(TNBC)においては、未だ明確な治療標的を同定できていないことが最大の問題であるが、その要因の一つは根底にある異常や病態が症例毎に大きく異なっていることにある。本研究ではTNBCの多様性をエピゲノムの観点から明らかにすることができたが、これらのデータは、TNBC症例をより精密に分類し、それぞれの病態に適した新規治療戦略を構築するための基盤データとして利用できると考えられる。

Research Products

• [Journal Article] HERC2 facilitates BLM and WRN helicase complex interaction with RPA to suppress G-quadruplex DNA. (2018)
  • Author(s): Wu W, Rokutanda N, Takeuchi J, Lai Y, Maruyama R, Togashi Y, Nishikawa H, Arai N, Miyoshi Y,Suzuki N, Saeki Y, Tanaka K, Ohta T.
  • Journal Title: Cancer Res. Volume: 78 Issue: 22 Pages: 6371-6385
  • DOI: 10.1158/0008-5472.can-18-1877
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer. (2018)
  • Author(s): Johmura Y, Maeda I, Suzuki N, Wu W, Goda A,Morita M, Yamaguchi K, Yamamoto M, Nagasawa S, Kojima Y, Tsugawa K, Inoue N, Miyoshi Y, Osako T Akiyama F, Maruyama R, Inoue JI, Fukukawa Y, Ohta T, Nkanishi M.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 12 Pages: 5603-5619
  • DOI: 10.1172/jci121679
  • Peer Reviewed / Open Access
• [Presentation] ATAC-seq analysis reveals epigenetic heterogeneity in breast cancer. (2019)
  • Author(s): Liying Yang, Tomoyoshi Nakadai, Reo Maruyama.
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research
  • Int'l Joint Research / Invited
• [Presentation] ATAC-seq法を用いたトリプルネガティブ乳癌のエピゲノム多様性の解析 (2018)
  • Author(s): 丸山玲緒、楊麗英、粂川昂平、中太智義
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] トリプルネガティブ乳癌のエピゲノム不均一性の解析 (2018)
  • Author(s): 丸山玲緒、楊麗英、粂川昂平、中太智義
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] ATAC-seq法を用いた乳がんのエピゲノム不均一性の解析 (2018)
  • Author(s): 楊麗英, 粂川昂平, 中太智義, 丸山玲緒.
  • Organizer: 第12回日本エピジェネティクス研究会年会
• [Presentation] ATAC-seq法によるトリプルネガティブ乳癌のエピゲノム多様性の解析 (2018)
  • Author(s): 丸山玲緒, 楊麗英, 田辺真彦.
  • Organizer: 第26回日本乳癌学会学術総会
• [Presentation] Epigenetic heterogeneity in triple-negative breast cancer (2018)
  • Author(s): Liying Yang, Kohei Kumegawa, Reo Maruyama.
  • Organizer: NCU Global Young Investigator Forum 2018
  • Int'l Joint Research
• [Presentation] トリプルネガティブ乳がんにおけるエピゲノム不均一性の解析 (2017)
  • Author(s): 粂川 昂平、楊 麗英、丸山 玲緒.
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Epigenetic heterogeneity in triple-negative breast cancer (2017)
  • Author(s): Reo Maruyama, Liying Yang, Kohei Kumegawa.
  • Organizer: Advanced in Breast Cancer Research (AACR)
  • Int'l Joint Research
• [Remarks]
  • URL: https://r-maruyama-lab.github.io/index.html