Targeting YB-1 activation pathway overcomes progressive breast cancer

• Project/Area Number: 19K16449
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Shinshu University (2020); Kyushu University (2019)
• Principal Investigator: Shibata Tomohiro 信州大学, 医学部, 日本学術振興会特別研究員 (40795986)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: YB-1 / 乳癌 / 内分泌治療耐性

Outline of Research at the Start

乳癌患者に対する薬物治療の継続は、しばしば耐性乳癌の出現を誘導し、再発・増悪を引き起こす。しかし、耐性獲得の詳細なメカニズムや克服治療は明らかになっていない。本研究では、乳癌の悪性化に関与するYB-1の活性化シグナルを明らかにし、それを標的とした新規乳癌克服治療薬の創出を目的としている。本研究の成果は、新規治療薬を提示することで進行性乳癌患者の予後の改善が期待でき、治療の向上に大きく貢献できる。

Outline of Final Research Achievements

Nuclear expression of Y-box binding protein-1 (YB-1) is closely correlated with clinical poor outcomes and drug resistance in breast cancer. Phosphorylated YB-1 (pYB-1) promotes expression of genes related to drug resistance and cell growth. A forthcoming problem to be addressed is whether targeting the phosphorylation of YB-1 overcomes antiestrogen resistance by progressive breast cancer. Here we found that increased expression of pYB-1 was accompanied by acquired resistance to antiestrogens, fulvestrant and tamoxifen. Forced expression of YB-1/S102E, a constitutive phosphorylated form, resulted in acquired resistance to fulvestrant. IHC analysis revealed that expression of pYB-1 and YB-1 was augmented in patients who experienced recurrence during treatment with adjuvant endocrine therapies. Taken together our findings suggest that pYB-1 represents a potential therapeutic target for treatment of antiestrogen resistant and progressive breast cancer.

Academic Significance and Societal Importance of the Research Achievements

ERα陽性乳癌の治療における内分泌治療耐性癌の耐性化メカニズムに関して様々な報告があるが、有効な耐性癌の予防薬や克服治療薬は未だ見いだされていない。本研究で、内分泌治療耐性患者検体及び乳癌細胞を駆使した検討から、活性化YB-1及びYB-1活性化シグナルが耐性癌の出現に関与していることを明らかにした。さらに、活性化YB-1標的薬が内分泌治療耐性乳癌の克服に有効であることを明らかにすることができた。本研究の成果が内分泌治療耐性乳癌治療の発展に貢献することを期待している。

Research Products

• [Journal Article] Selective Covalent Targeting of Mutated EGFR(T790M) with Chloroacetamide-Pyrimidines (2020)
  • Author(s): Mami Sato, Hirkazu Fuchida, Naoya Shindo, Keiko Kuwata, Keisuke Tokunaga, Guo Xiao-Lin, Ryo Inamori, Keitaro Horokawa, Kosuke Watari, Tomohiro Shibata, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo, Mayumi Ono, Akio Ojida
  • Journal Title: ACS Medicinal Chemistry Letters Volume: 11 Issue: 6 Pages: 1137-1144
  • DOI: 10.1021/acsmedchemlett.9b00574
  • Peer Reviewed
• [Journal Article] NDRG1 activates VEGF-A-induced angiogenesis through PLCγ1/ERK signaling in mouse vascular endothelial cells (2020)
  • Author(s): Watari Kosuke、Shibata Tomohiro、Fujita Hideaki、Shinoda Ai、Murakami Yuichi、Abe Hideyuki、Kawahara Akihiko、Ito Hiroshi、Akiba Jun、Yoshida Shigeo、Kuwano Michihiko、Ono Mayumi
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 107-107
  • DOI: 10.1038/s42003-020-0829-0
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Phosphorylation of Y-Box Binding Protein YBX1 by TAS0612 and Everolimus in Overcoming Antiestrogen Resistance (2020)
  • Author(s): Shibata Tomohiro、Watari Kosuke、Kawahara Akihiko、Sudo Tomoya、Hattori Satoshi、Murakami Yuichi、Izumi Hiroto、Itou Junji、Toi Masakazu、Akiba Jun、Akagi Yoshito、Tanaka Maki、Kuwano Michihiko、Ono Mayumi
  • Journal Title: Molecular Cancer Therapeutics Volume: 19 Issue: 3 Pages: 882-894
  • DOI: 10.1158/1535-7163.mct-19-0690
  • Peer Reviewed
• [Journal Article] Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma (2020)
  • Author(s): Ito Hiroshi、Watari Kosuke、Shibata Tomohiro、Miyamoto Tomofumi、Murakami Yuichi、Nakahara Yukiko、Izumi Hiroto、Wakimoto Hiroaki、Kuwano Michihiko、Abe Tatsuya、Ono Mayumi
  • Journal Title: Cancer Research Volume: 80 Issue: 2 Pages: 234-248
  • DOI: 10.1158/0008-5472.can-19-0438
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Y-box binding protein YB-1活性化シグナルを標的とした乳癌の内分泌治療耐性の新規克服治療 (2019)
  • Author(s): 柴田智博、渡公佑、河原明彦、和泉弘人、村上雄一、桑野信彦、小野眞弓
  • Organizer: 第23回日本がん分子標的治療学会学術集会
• [Presentation] The activated YB-1 as an effective therapeutic target in human progressive cancers (2019)
  • Author(s): Tomohiro Shibata, Kosuke Watari, Michihiko Kuwano, Mayumi Ono
  • Organizer: COLD SHOCK PROTEIN SYMPOSIUM 2019
  • Int'l Joint Research / Invited
• [Presentation] Y-box binding protein YB-1リン酸化シグナル阻害薬による乳癌の内分泌治療耐性克服 (2019)
  • Author(s): 柴田智博、渡公佑、河原明彦、主藤朝也、村上雄一、和泉弘人、秋葉純、桑野信彦、小野眞弓
  • Organizer: 第78回日本癌学会学術総会