Targeting YB-1 activation pathway overcomes progressive breast cancer

2020 Fiscal Year Final Research Report

• 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
• Keywords: YB-1 / 乳癌 / 内分泌治療耐性

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.

Free Research Field

がん生物学

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。