| Project/Area Number |
18K15252
|
|---|
| Research Category |
Grant-in-Aid for Early-Career Scientists
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Basic Section 50010:Tumor biology-related
|
|---|
| Research Institution | Tokyo Medical University |
|---|
Principal Investigator |
BAE Eunjin 東京医科大学, 医学部, 兼任助教 (40773388)
|
|---|
| Project Period (FY) |
2018-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
|
|---|
| Keywords | Breast Cancer / Chemoresistance / EMT / TGF-β / Smad2 / Smad3 / Linker phosphorylation / Breast cancer / TGF-beta / Smad / Phosphorylation / breast cancer / SMAD |
|---|
| Outline of Final Research Achievements |
Transforming growth factor (TGF)-β receptor-regulated Smads: Smad2 and Smad3 are phosphorylated at their C-terminal serine residues, which transduce canonical TGF-β signaling. This study has uncovered the novel roles of non-canonical signaling via linker phosphorylated Smad2 and Smad3 (pSmad2L and pSmad3L) in the pathogenesis of triple-positive breast cancer (TPBC) and triple-negative breast cancer (TNBC) in distinctive manners.
I have found that pSmad2L induced chemoresistance of TPBC. Inflammatory cytokines induced pSmad2L via the specific protein kinase and chemoresistance of TPBC. RNA sequencing of the TPBC cell line transfected with pSmad2L active and inactive mutants identified the target genes of pSmad2L to induce chemoresistance.
By contrast with pSmad2L, I have found that pSmad3L induced epithelial-mesenchymal transition (EMT) and chemoresistance of TNBC cell lines.
|
| Academic Significance and Societal Importance of the Research Achievements |
Smad2とSmad3のC末端リン酸化を介する古典的TGF-βシグナル伝達経路による乳癌病態制御機構については多くが解明されてきたが、本研究では、Smad2とSmad3のリンカー領域リン酸化による非古典的シグナル伝達経路が乳癌の化学療法抵抗性を誘導する新規の作用とその分子病理学的機序を明らかにした。
本研究成果は、乳癌化学療法抵抗性を防ぐ治療方法の開発につながる可能性を有する。
|
