| Project/Area Number |
17K15508
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | YB-1 / 乳癌 / 内分泌治療耐性 / ER / HER2 |
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| Outline of Final Research Achievements |
Despite considerable advances in the treatment of estrogen receptor alpha (ERα)-positive breast cancer, numerous patients develop recurrence during endocrine therapy. Drug resistance to various anticancer drugs is often correlated with enhanced nuclear expression of the Y-box binding protein-1 (YB-1) in breast cancer. In this study, fulvestrant resistant breast cancer cell lines (FR-1 and FR-2) showed markedly reduced expression of ERα and increased expression levels of pYB-1, pmTOR, pAKT, pp70S6K, and pS6. FR-1 and FR-2 showed collateral sensitivity to everolimus (an mTORC1 inhibitor). Furthermore, we demonstrated that pYB-1 directly promoted the ERα-independent cell growth of breast cancer cells. Finally, treatment with everolimus could overcome acquired resistance to antiestrogens through reduction of pYB-1 expression in vivo,
Based on these findings, we concluded that the pYB-1 represents an attractive therapeutic target for endocrine therapy resistant breast cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
ERα陽性乳癌の治療においてERα標的を標的とした内分泌治療の継続による耐性がんの出現が大きな克服すべき課題である。内分泌治療耐性メカニズムには、ERαの活性化変異やERα欠失、バイパスシグナルの活性化などが報告されているが、有効な克服治療は見いだされていない。本研究で、内分泌治療耐性乳癌細胞を駆使した検討から、リン酸化YB-1がERα発現を抑制し、増殖関連遺伝子の発現を上昇させることで、内分泌耐性を誘導することを明らかにした。さらに、YB-1リン酸化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、今後の研究の発展により乳癌治療の向上に大きく貢献できると考えられる。
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