Development of Notch4-targeted therapy for patients with HR-negative and HER2-negative breast cancer

• Project/Area Number: 25461983
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyushu University
• Principal Investigator: KUBO Makoto 九州大学, 大学病院, 助教 (60403961)
• Co-Investigator(Kenkyū-buntansha): KATANO Mitsuo 福岡女学院看護大学, 看護学部, 学長 (10145203) ; NAKANO Kenji 九州大学, 先端融合医療レドックスナビ研究拠点, 教授 (00315061) ; ONISHI Hideya 九州大学, 医学研究院, 准教授 (30553276)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: トリプルネガティブ乳癌 / Notchシグナル経路 / Notch4 / Stemness / Basal-like / BRCAness / Notch経路 / 浸潤性乳菅癌 / BRCA1ness

Outline of Final Research Achievements

This study shows that NOTCH4 receptor is a potential new therapeutic target for TNBC. First, NOTCH4 inhibition reduced proliferation and invasiveness in TNBC cells and reduced tumour volume and tumourigenicity, in vivo. Second, CD24 siRNA-transfected breast cancer cells (BCCs) demonstrated higher expression of Hedgehog signaling molecule, increased anchorage-independent proliferation, and enhanced invasiveness and superior tumorigenicity. DNA microarray analysis identified STAT1 as a relationship between CD24 and SHH. CD24 siRNA-transfected BCCs with concurrent STAT1 inhibition exhibited decreased SHH expression. Finally, we focused on instability of TNBC. Of the 71 TNBCs, 59 tumors (83%) were the basal-like phenotype. The results of the MLPA assays showed that 37 (62.7%) tumors had a BRCAness. Our study proved that TNBCs involve the stemness which activates Notch signaling and the BRCAness which increases gene instability.

Research Products

• [Journal Article] CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells. (2016)
  • Author(s): Suyama K, Onishi H, Imaizumi A, Shinkai K, Umebayashi M, Kubo M, Mizuuchi Y, Oda Y, Tanaka M, Nakamura M, Katano M.
  • Journal Title: Cancer Letters Volume: 374(1) Issue: 1 Pages: 44-53
  • DOI: 10.1016/j.canlet.2015.12.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] NOTCH4 is a potential therapeutic target for triple-negative breast cancer. (2014)
  • Author(s): Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M, Katano M.
  • Journal Title: Anticancer Res. Volume: 34(1) Pages: 69-80
  • Peer Reviewed
• [Presentation] TNBC-correlation with other markers to predict outcome (2016)
  • Author(s): Makoto Kubo
  • Organizer: The 14th Asian Breast Diseases Association Meeting & Symposium
  • Place of Presentation: スカラエスパシオ（福岡県・福岡市）
  • Year and Date: 2016-09-03
  • Int'l Joint Research / Invited
• [Presentation] Hh経路制御による乳癌幹細胞制御療法の開発 (2016)
  • Author(s): 巣山 久実、大西 秀哉、今泉 晃、片野 光男
  • Organizer: 第116回 日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2016-04-15
• [Presentation] BRCAness and PD-L1 expression of Basal-like and Non-Basal-like Triple Negative Breast Cancer (2015)
  • Author(s): Hitomi Mori, Makoto Kubo, Mai Yamada, Masaya Kai, Masayuki Okido, Tomofumi Osako, Reiki Nishimura, Nobuyuki Arima, Yoshinao Oda, Masafumi Nakamura
  • Organizer: The 38th San Antonio Breast Cancer Symposium (2015)
  • Place of Presentation: Henry B. Gonzalez Convention Center・サンアントニオ（米国）
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] 乳癌におけるCD24分子発現の意義：CD24分子発現とHh経路活性化の連関解析 (2015)
  • Author(s): 巣山 久実、大西 秀哉、今泉 晃、新海 健太郎、甲斐 昌也、田中 晴生、久保 真、田中 雅夫、片野 光男
  • Organizer: 第115回 日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-04-16
• [Presentation] Hh経路制御による乳癌幹細胞制御療法の開発：CD24分子発現とHh経路活性化の連関解析 (2014)
  • Author(s): 巣山久実、大西秀哉、甲斐昌也、田中晴生、久保真、新海健太郎、永松伊織、松下章次郎、森藤良浩、今泉晃、田中雅夫、片野光男
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2014-04-04
• [Presentation] 乳癌細胞におけるCD24分子発現とHh経路活性化の連関の解析 (2013)
  • Author(s): 巣山 久実、大西 秀哉、甲斐 昌也、田中 晴生、久保 真、永松 伊織、今泉 晃、田中 雅夫、片野 光男
  • Organizer: 第２６回日本バイオセラピィ学会学術集会
  • Place of Presentation: いわて県民情報交流センターアイーナ（盛岡市）
• [Presentation] トリプルネガティブ乳癌に対する新たな治療標的の同定：Notchシグナル系 (2013)
  • Author(s): 永松 伊織、甲斐 昌也、松下 章次郎、大西 秀哉、久保 真、中野 賢二、田中 雅夫、片野 光男
  • Organizer: 第２６回日本バイオセラピィ学会学術集会
  • Place of Presentation: いわて県民情報交流センターアイーナ（盛岡市）