2020 Fiscal Year Research-status Report
Phosphorylation status-dependent roles of TGF-beta receptor-regulated SMADs in inflammation-induced chemoresistance of breast cancer
| Project/Area Number |
20K16368
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
裴 恩真 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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| Keywords | Breast cancer / Chemoresistance / TGF-beta / IL-6 / SMAD2 / Linker phosphorylation / STAT |
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| Outline of Annual Research Achievements |
<Plan 1-1 Effects of phosphorylation status of R-SMADs on breast cancer chemoresistance> I have found that IL-6 rendered MCF7 TPBC and MDA-MB231 TNBC cells resistant to paclitaxel and tamoxifen via linker phosphorylation of SMAD2 at serine 255 residues (pSMAD2L S255).
<Plan 1-2 Evaluation of chemosensitivity regulated by phosphorylation status of R-SMADs in mouse breast cancer metastasis model> I have changed the plan to add 4T1 BALB/c mouse breast cancer model to the originally proposed human breast cancer xenograft model to investigate anti-tumor immunity as well. I have generated the cells lines expressing the active or inactive mutants of pSMAD2L S255 (S255D or S255A) using adeno-associated virus (AAV) system as described below.
<Plan 2 Identification of the target genes regulated by R-SMADs to regulate STAT3-induced chemoresistance> I have generated the AAV vectors expressing constitutively active or inactive mutants of pSMAD2L S255 (S255D or S255A). I have run RNA-seq using pSMAD2L S255D and S255A-infected MCF7 cells with control.
<Plan 3 The signaling mechanisms how linker-phosphorylated R-SMADs regulate STAT3-induced chemoresistance of TNBC and non-TNBC cell lines> I have found that JNK induced pSMAD2L S255 and thereby chemoresistance of MCF-7 cells.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
As stated in the summary, I have performed the project as proposed.
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| Strategy for Future Research Activity |
I will especially focus on <Plan 3> the novel signaling mechanisms how pSMAD2L and STAT3 induced chemoresistance of breast cancer using both in vitro and in vivo systems to finish the project.
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| Causes of Carryover |
Due to the pandemic, I could not spend the whole of FY2020 budget. I will spend the balance for sequencing and purchasing the antibodies and reagents required for the breast cancer mouse model and mechanistic studies this year.
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