| Project/Area Number |
20K16368
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
Bae Eunjin 東京医科大学, 医学部, 兼任助教 (40773388)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 乳癌 / 治療抵抗性 / TGF-beta / SMAD / リン酸化 / トランスフォーミング増殖因子β（TGF-β） / 炎症 / Breast cancer / Chemoresistance / IL-6 / SMAD2 / Linker phosphorylation / STAT / Breast Cancer / Proinflammatory cytokine / SMAD phosphorylation |
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| Outline of Research at the Start |
TGF-β/SMADs and IL-6/STAT3 pathways are crucial for breast carcinogenesis.
However, the mechanisms how SMADs and STAT3 form a network to induce inflammation-induced chemoresistance are unknown.
To elucidate how phosphorylation status of SMADs and STAT3 regulate chemosensitivity of breast cancers, I will investigate <1> the effects of phosphorylation status of SMAD2/3 and STAT3-induced chemoresistance, <2> the target genes of phosphorylated SMAD2/3 and STAT3 to regulate STAT3-induced chemoresistance, <3> the signaling mechanisms how phosphorylated SMAD2/3 regulate STAT3-induced chemoresistance.
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| Outline of Final Research Achievements |
Transforming growth factor (TGF)-β plays crucial roles in cancer progression and metastasis. I have investigated the mechanisms how TGF-β regulates chemoresistance and chemosensitivity of breast cancer in this study.
The linker region of TGF-β signaling molecule, SMAD was phosphorylated in human breast cancer tissues, which was not observed in normal tissues. Breast cancer cell lines transfected with various mutants of SMAD revealed the site and upstream signaling pathway responsible for chemoresistance. Comprehensive analyses using RNA-seq and ChIP-seq showed the gene regulatory network by the identified pathway. I have optimized the mouse orthotopic transplant breast cancer model using syngeneic mouse breast cancer cell line transfected with the identified mutants using the adeno-associated virus vector for in vivo imaging.
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| Academic Significance and Societal Importance of the Research Achievements |
乳がんは本邦において最も多い女性のがんで３０-６４歳の世代ではがんによる死亡数第一位である。抗がん薬に対する治療抵抗性は予後を改善するために解決すべき課題である。本研究では、がんの進展と転移に重要な働きを及ぼすサイトカインであるTGF-βの細胞内信号伝達経路がどのように治療抵抗性を調節するのかを明らかにした。本研究の成果は、乳がんの抗がん薬抵抗性を抑えて有効性を高める新規治療方法の開発につながる。
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