2016 Fiscal Year Final Research Report
Involvement of TGF-beta/SMAD signaling in trastuzumab resistance
| Project/Area Number |
26461945
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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 | Osaka University |
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Principal Investigator |
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| Research Collaborator |
CHIHARA Yoko
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Keywords | 乳癌 / HER2 / TGF-beta / SMAD3 / トラスツズマブ / ラパチニブ / 癌幹細胞 |
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| Outline of Final Research Achievements |
Purpose: The aim of this study was to investigate the effects of TGFβ and its downstream SMAD pathway on resistance to anti-HER2 drugs.
Results: We found that continuous activation of the TGFβ-SMAD3 pathway induced resistance to anti-HER2 drugs and cancer stem cell traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFβ required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. Small inhibitor of SMAD3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells.
Conclusions: This study indicates that the TGFβ-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs.
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| Free Research Field |
乳腺外科学
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