Involvement of TGF-beta/SMAD signaling in trastuzumab resistance

• Project/Area Number: 26461945
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Osaka University
• Principal Investigator: Shimoda Masafumi 大阪大学, 医学系研究科, 助教 (30644455)
• Co-Investigator(Kenkyū-buntansha): 直居 靖人 大阪大学, 医学系研究科, 助教 (30646211)
• Research Collaborator: CHIHARA Yoko
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 乳癌 / HER2 / TGF-beta / SMAD3 / トラスツズマブ / ラパチニブ / 癌幹細胞 / TGFβ / trastuzumab / HER2陽性乳癌 / 抗HER2抗体 / TGF-β

Outline of Final Research Achievements

Purpose: The aim of this study was to investigate the effects of TGFβ and its downstream SMAD pathway on resistance to anti-HER2 drugs.
Results: We found that continuous activation of the TGFβ-SMAD3 pathway induced resistance to anti-HER2 drugs and cancer stem cell traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFβ required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. Small inhibitor of SMAD3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells.
Conclusions: This study indicates that the TGFβ-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs.

Research Products

• [Presentation] TGFβ-SMAD3 経路の持続的活性化による抗 HER2 薬に対する 耐性化の誘導 (2016)
  • Author(s): 千原陽子
  • Organizer: 第２４回日本乳癌学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2016-06-16
• [Presentation] Importance of TGFβ-SMAD3 axis in resistance to anti-HER2 drugs (2015)
  • Author(s): 下田雅史
  • Organizer: San Antonio Breast Cancer Symposium 2015
  • Place of Presentation: San Antonio, Texas, USA
  • Year and Date: 2015-12-08
  • Int'l Joint Research