Analysis of mechanisms of breast cancer stem cells using mammary tumor model mice

• Project/Area Number: 15K21438
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry; Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: YAMAMOTO MIZUKI 東京大学, 医科学研究所, 特任助教 (90750365)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 乳癌 / 癌悪性化 / 癌幹細胞 / 上皮間葉転換 / 乳癌幹細胞 / 乳腺上皮細胞

Outline of Final Research Achievements

Breast cancer is a heterogeneous disease classified into two biological subtypes. Basal-like subtype breast cancer, which is ER-, PR-, ERBB2- (TNBC) phenotype, shows higher malignancy than luminal type, and exhibits poor prognoses against various methods of therapy. In this study, we focused on the cancer stem cells (CSC), a malignant sub-population in the tumor. Using activated Ras and p53 knockout mammary epithelial cells, we found that a portion of cancer cells undergo epithelial to mesenchymal transition (EMT), one of mechanism of CSC generation. Therefore, we analyzed the mechanism of EMT and MET and demonstrate that the two populations significantly enhance the transition of cells from the other population to their own. We also demonstrate that primary breast cancer cells underwent EMT. Further studies to elucidate the molecular mechanisms governing the dynamic EMT and MET observed in breast cancer cells must be pursued to develop effective therapeutic strategies against TNBC.

Research Products

• [Journal Article] Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer. (2017)
  • Author(s): Yamamoto, M., Sakane, K., Tominaga, K., Gotoh, N., Niwa, T., Kikuchi, Y., Tada, K., Goshima, N., Semba, K. and Inoue, J.
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 6 Pages: 1210-1222
  • DOI: 10.1111/cas.13246
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] TRAF6は乳腺幹細胞の維持および乳腺上皮細胞の細胞死抑制によって妊娠期の乳腺発達を促進する (2016)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Differential roles of NF-kB activation in mammary gland development and breast cancer malignancy (2016)
  • Author(s): Mizuki Yamamoto, Jun-ichiro Inoue
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] TRAF6 regulates pregnancy-induced mammary gland development and maintenance of epithelial stem cells (2016)
  • Author(s): Mizuki Yamamoto, Jun-ichiro Inoue
  • Organizer: KEYSTONE SYMPOSIA
  • Place of Presentation: Breckenridge, Colorado (USA)
  • Year and Date: 2016-03-06
• [Presentation] 妊娠期の乳腺成熟および幹細胞維持におけるTRAF6の役割 (2015)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド(兵庫県・神戸)
  • Year and Date: 2015-12-01
• [Presentation] Non-Cell-Autonomous Regulation of Epithelial-Mesenchymal Transition in Breast Cancer (2015)
  • Author(s): 山本瑞生、井上純一郎
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: NAGOYA CONGRESS CENTER(愛知県・名古屋)
  • Year and Date: 2015-10-08