Identification of recurrent genetic and epigenetic alterations of SALL3 in TNBC by comprehensive genomic analysis

• Project/Area Number: 18K07200
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: MATSUSHITA Yosuke 徳島大学, 先端酵素学研究所(プロテオ), 助教 (70634450)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: トリプルネガティブ乳癌 / TNBC / 乳癌

Outline of Final Research Achievements

Triple-negative breast cancers (TNBC) is a highly heterogeneous disease with problems of early recurrence and resistance to therapeutic agents. In this study, SALL3 showed frequent inactivation (frequent downregulation / mutation). By analyzing the molecular mechanism of TNBC, we attempted to identify new biological properties of TNBC. As a result, the frequent decrease in SALL3 expression is mainly regulated by promoter methylation, and this correlation is only controlled in TNBC. In addition, it was shown that SALL3 regulates the expression of its target gene by forming a transcription complex, and that the downregulation of SALL3 or target-gene contributes to resistance to paclitaxel or docetaxel.

Academic Significance and Societal Importance of the Research Achievements

TNBCはERやHER2陽性サブタイプと異なり, 明確な治療標的が存在しないため, 内分泌療法や抗HER2療法の効果が期待できない. さらに, 概して予後が悪く, 早期再発も多いことから, TNBCの予後改善を目的とした治療法の確立, メカニズムの解明は急務であった. 高頻度に不活化 (発現低下・変異) を認めた SALL3の分子機構を解析することで, TNBCの新たな生物学的特徴付けは, 治療法確立に繋がることが期待されるため, 本研究の社会的意義は大きいと考えられる.

Research Products

• [Presentation] Frequent downregulation of SALL3 by genetic and epigenetic alterations is involved in progression and chemoresistance of triple negative breast cancers (2019)
  • Author(s): Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] トリプルネガティブ乳癌におけるがん抑制因子SALL3の不活化機構の解明 (2019)
  • Author(s): 松下洋輔、小松正人、吉丸哲郎、井本逸勢、鈴木拓、片桐豊雅
  • Organizer: 第23回日本がん分子標的治療学会学術集会
• [Presentation] The regulation of glutaminolysis via RHBDL2 is associated with malignant and chemoresistance in TNBC (2019)
  • Author(s): Yosuke Matsushita, Kazumasa Okumura, Masato Komatsu, Ryuichiro Kimura, Tetsuro Yoshimaru, Masaya Ono, Junko Honda, Akira Tangoku, Yasuo Miyoshi, Mitsunori Sasa, Toyomasa Katagiri
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] The exploration of novel susceptibility genes associated with Japanese familial breast cancer by whole exome sequencing (2019)
  • Author(s): 松下洋輔・高橋 定子・小松正人・清谷一馬・吉丸哲郎 ・三好康雄・本田純子 ・紺谷 桂一・大住省三・笹三徳・片桐豊雅
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] Frequent downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple negative breast cancers (2018)
  • Author(s): Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Hiromu Suzuki, Yasuo Miyoshi, Mitsunori Sasa and Toyomasa Katagiri
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] トリプルネガティブ乳がんの包括的ゲノム解析 (2018)
  • Author(s): 松下洋輔, 片桐豊雅
  • Organizer: 第２回質量分析インフォマティクスハッカソンシンポジウム
  • Invited
• [Presentation] Downregulation of SALL3 by recurrent genetic and epigenetic alterations is involved in triple negative breast cancers (2018)
  • Author(s): Yosuke Matsushita, Masato Komatsu, Kazuma Kiyotani, Tetsuro Yoshimaru, Takeshi Niinuma, Hiromu Suzuki, Junko Honda, Issei Imoto, Akira Tangoku, Yasuo Miyoshi, Mitsunori Sasa and Toyomasa Katagiri
  • Organizer: 第77回日本癌学会学術総会