초록 ▼

본 연구는 유방암에서 trastuzumab 내성획득은 HER2의 과다 발현된 유방암 조직에서 FAS 발현증가와 관련이 있으며, 이는 Pin1에 의한 SREBP1c 전사조절의 활성이 FAS 발현을 증가시키는 신호전달 과정에 기인함을 규명하였음. 나아가 Pin1은 히스톤 H3의 lysine 9의 methyltransferase인 SUV39H1과 상호작용하여 ubiquitination을 통한 단백질 분해를 촉진시키고 히스톤 H3의 methylation 조절을 통한 유방암 발생과정에 관여함을 규명함. 본 연구과제의 성공적 연구결과는 HER

본 연구는 유방암에서 trastuzumab 내성획득은 HER2의 과다 발현된 유방암 조직에서 FAS 발현증가와 관련이 있으며, 이는 Pin1에 의한 SREBP1c 전사조절의 활성이 FAS 발현을 증가시키는 신호전달 과정에 기인함을 규명하였음. 나아가 Pin1은 히스톤 H3의 lysine 9의 methyltransferase인 SUV39H1과 상호작용하여 ubiquitination을 통한 단백질 분해를 촉진시키고 히스톤 H3의 methylation 조절을 통한 유방암 발생과정에 관여함을 규명함. 본 연구과제의 성공적 연구결과는 HER2 억제 항암제의 내성치료분야에서 Pin1 단백질을 표적으로 하는 신약개발의 기술의 기반 구축에 활용 될 것임.

Abstract ▼

I. Specific Aims and Needs for Research
Clinicians are faced with two main problems when using HER2 inhibitors against HER2-driven breast cancer tumors. Our groups plan to reveal the basic mechanism of therapeutic resistance and cardiotoxicity elicited by HER2 inhibitors, and to overcome breast c

I. Specific Aims and Needs for Research
Clinicians are faced with two main problems when using HER2 inhibitors against HER2-driven breast cancer tumors. Our groups plan to reveal the basic mechanism of therapeutic resistance and cardiotoxicity elicited by HER2 inhibitors, and to overcome breast cancer resistance to HER2 inhibitor as targeting new therapeutic marker.
Ⅱ. Research Design and Methods
1) Elucidation of molecular mechanism of therapeutic resistance and cardiotoxicity of HER2-inhibiting anticancer drug:The screening of proteins related with therapeutic resistance and cardiotoxicity of HER2-inhibiting anticancer drug
2) Development of new anticancer drug to overcome therapeutic resistance and cardiotoxicity of HER2-inhibiting anticancer drug: Identify promising new drug candidates (phytochemicals) to overcome therapeutic resistance
3) In vivo evaluation of new anticancer drug to overcome therapeutic resistance and cardiotoxicity of HER2-inhibiting anticancer drug: In-vivo evaluation of therapeutic effects in mouse model of cancer
Ⅲ. Research Design and Methods
1) STEP 1
- Mammalian-two hybrid screening for elucidating the target protein mediating Herceptin resistance
- Elucidation of COT-Pin1 protein-protein interaction and the molecular mechanism of COT-induced Pin1 phosphorylation
- Elucidation of Pin1-AMPK protein-protein interaction and the molecular mechanism of Pin1-induced AMPK phosphorylation
- Elucidation of anti-tumorigenic effect of AMPK
2) STEP 2
- Elucidation of inhibition of Pin1 and FAS levels by trastuzumab
- Elucidation of Pin1-SUV39H1 protein-protein interaction and the molecular mechanism of Pin1-induced SUV39H1 phosphorylation
- Elucidation of Pin1-induced breast tumorigenesis via regulation of SUV39H1
- Elucidation of the correlation between Pin1 and SUV39H1 in breast cancer
3) STEP 3
- Elucidation of Pin1-induced FAS expression via SREBP1c promoter
- Elucidation of Pin1-AKT-SREBP1c-FAS signalling on the transtuzumab-induced apoptosis in breast cancer cells
- Elucidation of the correlation between Pin1 and FAS in breast cancer
Ⅳ. Anticipated results, Interpretation, and Future plans
1) Providing mechanistic knowledge of therapeutic resistance of anti-cancer drugs by comparing different biological systems
2) Leading the field of therapeutic resistance of anti-cancer drugs by applying advanced research techniques in a collaborative manner
3) It will develop the phytochemicals targeting breast cancer as well as diabetes/obesity.