Study for molecular basis of trastuzumab-resistance and the development of novel therapeutic strategies.

• Project/Area Number: 24591901
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kansai Medical University (2013-2014); Kyoto University (2012)
• Principal Investigator: SUGIE Tomoharu 関西医科大学, 医学部, 教授 (70335264)
• Co-Investigator(Kenkyū-buntansha): SUZUKI Eiji 京都大学, 医学研究科, 助教 (00612897) ; SATO Fumiaki 京都大学, 医学研究科, 准教授 (20467426)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 乳癌 / HER2 / トラスツズマブ / 耐性 / ＡＤＣＣ / ADCC / トラスツズマブ耐性

Outline of Final Research Achievements

HER2-targeted therapy using trastuzumab has dramatically improved the prognosis of HER2-positive breast cancer. However, it becomes the important clinical issue how to overcome tastuzumab-resistant breast cancer. In this study, we addressed the molecular mechanism for acquired resistance to trastuzumab which can activate antibody dependent cell mediated cytotoxicity (ADCC). Gene expressing profile using ADCC-resistant breast cancer cell line showed that vacuolar type ATPase (vATPase) which drives active membrane transport was associated with ADCC-resistance. ATP6V1B1 gene　coding subunit B1 might be specifically responsible for acquired resistance in terms of perforin/granzyme pathway.

Research Products

• [Journal Article] Immune-based mechanism in the treatment against breast cancer (2015)
  • Author(s): Tomoharu Sugie
  • Journal Title: Japanese J Breast Cancer Volume: 30 Pages: 95-100
• [Journal Article] The killer cell Ig-like receptor 2DL4 expression in human mast cells and its potential role in breast cancer invasion. (2015)
  • Author(s): Ueshima C, Kataoka TR, Hirata M, Furuhata A, Suzuki E, Toi M, Tsuruyama T, Okayama Y, Haga H
  • Journal Title: Cancer Immunol Res Volume: CIR-14 Pages: 0199-0199
  • Peer Reviewed
• [Journal Article] Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients (2015)
  • Author(s): Suzuki E, Kataoka T, Hirata M, Kawaguchi K, Nishie M, Haga H, Toi M
  • Journal Title: BMC Cancer Volume: 15 Issue: 1 Pages: 39-39
  • DOI: 10.1186/s12885-015-1041-3
  • NAID: 120005758423
  • Peer Reviewed / Open Access
• [Journal Article] Effects of zoledronic acid and the association between its efficacy and \gamma\delta T cells in postmenopausal women with breast cancer treated with preoperative hormonal therapy: a study protocol (2014)
  • Author(s): Sumi E, Sugie T, Yoshimura K, Tada H, Ikeda T, Suzuki E, Tanaka Y, Teramukai S, Shimizu A, Toi M, Minato N
  • Journal Title: Journal of Translational Medicine Volume: 12 Issue: 1 Pages: 310-310
  • DOI: 10.1186/s12967-014-0310-2
  • Peer Reviewed / Open Access
• [Presentation] 乳がん腫瘍浸潤リンパ球の意義と今後の課題 (2015)
  • Author(s): 杉江知治
  • Organizer: 日本乳癌学会
  • Place of Presentation: 東京・東京国際フォーラム
  • Year and Date: 2015-07-02 – 2015-07-04
  • Invited
• [Presentation] Down regulation of ATP6V1B1 in HER2-overexpressing human breast cancer cell line leads resistance against trastuzumab mediated antibody dependent cellular cytotoxicity (2015)
  • Author(s): Nishie Ｍ, Suzuki E, Kawaguchi K, Sakamoto K, Fukushima Y,Hattori M, Sugie T, Toi M
  • Organizer: AACR Annual Meeting 2015
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-19 – 2015-04-22
• [Presentation] Loss of HER2 via trogocytosis by CD14+ cells in HER2 overexpressing breast cancer cells are associated with diminishing of trastuzumab mediated antibody dependent cellular cytotoxicity. (2014)
  • Author(s): Suzuki E, Nishie M, Kawaguchi K, Tanaka S, Toi M
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Trogocytosis of HER2 overexpressing human breast cancer cell lines (2014)
  • Author(s): Aratake J, Suzuki E, Uehiro N, Kawaguchi K, Tanaka S, Nishie M, Sato F, Toi M
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] High neuropilin-1 expression on monocytes is positively associated with trastuzumab-mediated antibody-dependent cellular cytotoxicity of the HER2-overexpressing breast cancer cell line (2014)
  • Author(s): Kawaguchi K, Suzuki E, Kawashima M, Toi M
  • Organizer: AACR Annual Meeting 2014
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] 乳癌におけるトラスツズマブを介した抗体依存性細胞傷害活性における単球とNK細胞の役割 (2014)
  • Author(s): 鈴木栄治, 荒武淳一, 河口浩介, 田中 直, 西江万梨子, 平田勝啓, 片岡 竜貴, 戸井雅和
  • Organizer: 日本外科学会
  • Place of Presentation: 京都・国立京都国際会館・グランドプリンスホテル京都
  • Year and Date: 2014-04-03 – 2014-04-05
• [Presentation] High neuropilin-1 expression on monocytes is positively associated with trastuzumab-mediated antibody-dependent cellular cytotoxicity of the HER2-overexpressing breast cancer cell line. (2014)
  • Author(s): Ｋａｗａｇｕｃｈｉ Ｋ， Ｓｕｚｕｋｉ Ｅ， ｅｔ ａｌ．
  • Organizer: ＡＡＣＲ ａｎｎｕａl ｍｅｅｔｉｎｇ
  • Place of Presentation: San Diego, USA
• [Presentation] Loss of HER2 via trogocytosis by CD14+ cells in HER2 overexpressing breast cancer cells are associated with diminishing of trastuzumab mediated antibody dependent cellular cytotoxicity. (2014)
  • Author(s): Suzuki E, Nishie M, Kawaguchi K, et al.
  • Organizer: ＡＡＣＲ ａｎｎｕａl ｍｅｅｔｉｎｇ
  • Place of Presentation: San Diego, USA
• [Presentation] ヒト乳癌細胞がトラスツズマブを介した抗体依存性細胞傷害活性に対する耐性能を獲得するメカニズムの解明 (2013)
  • Author(s): 鈴木栄治、佐藤史顕、河口浩介、杉江知治、戸井雅和
  • Organizer: 日本乳癌学会
  • Place of Presentation: 浜松
• [Presentation] Trastuzumabを介した抗体依存性細胞障害活性(ADCC)耐性乳癌細胞株の樹立 (2012)
  • Author(s): 鈴木栄治、佐藤史顕、竹内恵、上野貴之、杉江知治、戸井雅和
  • Organizer: 日本乳癌学会
  • Place of Presentation: 熊本