Molecular mechanisms responsible for the development of acquired resistance to endocrine therapy in breast cancer
| Project/Area Number |
17K10566
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
森谷 卓也 川崎医科大学, 医学部, 教授 (00230160)
鹿股 直樹 川崎医科大学, 医学部, 准教授 (60263373)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 乳癌 / 内分泌療法 / 耐性 / マイクロアレイ / エストロゲン / HER4 / CXCR4 / 癌幹細胞 / 細胞株 / エストロゲン枯渇 / 抗エストロゲン薬 / 低酸素 / 抵抗性 / エストロゲン受容体 / ヘッジホッグシグナル / 内分泌療法耐性 / 低酸素微小環境 / ヘッジホッグシグナル伝達経路 |
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| Outline of Final Research Achievements |
We have developed endocrine-resistant breast cancer models using estrogen-sensitive MCF-7 cells. They were cultivated under an estrogen-deprived condition or exposure to an antiestrogen for over six months. Long-term estrogen-deprived (LTED) and fulvestrant (FUL)-resistant cells were established. An mRNA expression microarray revealed, 1) LTED cells showed an up-regulation of estrogen receptor (ER) signaling pathway, hypersensitivity to estrogen and an increase in cancer stem cell population. 2) FUL-resistant cells showed a down-regulation of ER signaling pathway, estrogen-insensitivity, up-regulation of hedgehog signaling pathway and increased expression levels of human epidermal growth factor receptor (HER) 1 and HER2. Increased expression levels of CXCR4 and HER4 were commonly observed in the LTED and FUL-resistant cells. We have been involved in exploratory studies on clarifying if these agents may overcome endocrine-resistance in the LTED and FUL-resistant breast cancer cells.
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| Academic Significance and Societal Importance of the Research Achievements |
乳癌の内分泌療法耐性の原因としては、細胞内外の増殖関連シグナルが活性化が重要である。本研究においてもHERファミリーのHER1, HER2, HER4の発現増加が確認された。E枯渇下及びフルベストラント曝露下におけるHER4の発現増加は、我々の知る限り初めての報告となる。HER4のシグナルを抑制するneratinibが内分泌療法耐性の克服に役立つ可能性がある。CXCR4は、癌細胞の浸潤や転移に関わる因子として注目されているが、癌幹細胞の生存や増殖にも関与している。CXCR4の働きを特異的に阻害するCXCR4阻害薬プレリキサホルはすでに臨床導入されており、内分泌療法耐性乳癌への応用も可能である。
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Report
(4 results)
Research Products
(31 results)
