| Project/Area Number |
17K10551
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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 | The University of Tokushima |
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Principal Investigator |
YOSHIMARU Tetsuro 徳島大学, 先端酵素学研究所(プロテオ), 准教授 (80424729)
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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: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 乳癌 / 活性酸素 / 薬剤耐性 / ミトコンドリア / HER2陽性乳癌 / 治療耐性 / 活性酸素種 |
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| Outline of Final Research Achievements |
We previously demonstrated that Brefeldin A-Inhibited Guanine nucleotide-exchange protein 3 (BIG3) functions as an A-kinase anchoring protein that binds PKA and PP1Cα in luminal-type breast cancers, thereby dephosphorylating and inactivating tumor suppressor, prohibitin2 (PHB2). We developed stERAP, a peptide inhibitor targeting the BIG3-PHB2 interaction, resulting in growth suppression through transcriptional regulation by the nuclear-translocation of PHB2. Notably, we newly observed that BIG3-PHB2 complex is localized in the mitochondria of refractory breast cancer cells, and regulates the mitochondrial reactive oxygen species (MtROS). Treatment with stERAP suppressed the MtROS production by estrogen stimulation, leading to global suppression efficacy of gene expression. It is suggested that regulation of MtROS production by mitochondrial BIG3-PHB2 complexes contribute to malignancy and/or acquired resistance to hormone therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
ホルモン依存性乳癌の治療は主に内分泌療法が施行されるが、奏功症例でも長期服用による耐性獲得を生じてしまい、二次内分泌療法がほとんど奏功せず、化学療法に頼らざるを得ない。これらの原因として、エストロゲン受容体（ERα）の陰転化、細胞膜直下のERαと膜型受容体のクロストークよるリン酸化カスケードの活性化など複数のエストロゲン・シグナルの活性化や血管新生因子の発現亢進などが報告されているが、その解明には未だ至ってない。したがって、ホルモン療法耐性獲得機序の包括的な解明は、効果的な治療成績の向上に繋がり、多大な社会的、経済的インパクトを提供できると考えられる。
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