초록 ▼

1. BRCA1결실/에스트로젠 처치 하에서 세포생장신호의 증가 (p-Rb, p-AKT의 증가), 세포사신호의 감소 (p53, p-CHK2, pATM의 증가), DNA 손상감지신호 (g-H2AX)의 감소 관찰되며 이를 통해 genetic instability가 축적된 세포의 생장이 가능하리라 추정됨.
2. Brca1돌연변이 쥐의 에스트로젠 처치는 발생학적 발달이 늦은 유방조직의 생장을 촉진함.
3. Brca1의 돌연변이에 의해 발생된 유방의 이상에서 암의 진행에 비례하는 Akt의 인산화 신호의 증가가 보이고 Akt의 위치가

1. BRCA1결실/에스트로젠 처치 하에서 세포생장신호의 증가 (p-Rb, p-AKT의 증가), 세포사신호의 감소 (p53, p-CHK2, pATM의 증가), DNA 손상감지신호 (g-H2AX)의 감소 관찰되며 이를 통해 genetic instability가 축적된 세포의 생장이 가능하리라 추정됨.
2. Brca1돌연변이 쥐의 에스트로젠 처치는 발생학적 발달이 늦은 유방조직의 생장을 촉진함.
3. Brca1의 돌연변이에 의해 발생된 유방의 이상에서 암의 진행에 비례하는 Akt의 인산화 신호의 증가가 보이고 Akt의 위치가 핵으로 이동하는 현상을 보이고 에스트로젠은 BRCA1의 결손시 세포내에서 AKT의 축적과 활성화를 촉진
4. BRCA1의 결손시 에스트로젠의 처리에 의해 생기는 세포주기조절의 이상, cyclin D1의 과도한 축적, 세포증식은 AKT의 저해를 통해 회복됨.
5. Brca1 돌연변이 마우스에서 생성된 유방암의 발생은 Akt의 발현 억제시 암 발생이 저하.

Abstract ▼

I.Research Purpose
1. We will investigate the molecular consequence of Brca1-deficient tumorigenesis under the influence of estrogen to find out suitable target of this process.
2. Success of this study will provide the option of BRCA1-deficient breast cancer treatment and prevention by using

I.Research Purpose
1. We will investigate the molecular consequence of Brca1-deficient tumorigenesis under the influence of estrogen to find out suitable target of this process.
2. Success of this study will provide the option of BRCA1-deficient breast cancer treatment and prevention by using ER-positive treatment.
3. Currently, it is not easy to try the clinical study for identification and grouping of BRCA1 cases. Thus, to get the qualified result of this study, we will use mice model of Brca1 KO with the favor of in vivo study.
Ⅱ.Research Procedure
1. Developing of in vitro model: To downregulate the Brca1, we used the expression knockdown by introducing siRNA and shRNA. Then, we analyzed the DNA damage, cell proliferation, and apoptosis, and performed the western blot from the extracts of cultured cells.
2. Developing of in vivo model: As the backbone of mice model, we used Brca1co/coMMTV-cre mutant mice. To see the effect of estrogen and obesity, we injected the estrogen in solution or slowly released bead, and feed the mice in high fat diet. Mice were monitored at least twice a week for possible symptoms related to illness and tumor formation. When mice developed symptoms and tumors, tissues were collected for further analysis. For histology analysis, tissues were fixed, embedded in paraffin wax, and the further analyzed.
3. Target validation: when we identified the target protein, we inhibited its function by shRNA knockdown.
Ⅲ.Results
1. Estrogen enhanced the accumulation and activation of AKT in the loss of BRCA1.
2. Inhibition of AKT restored the abnormalities of cell cycle deregulation, cyclin D1 accumulation, and hyperproliferation caused from the estrogen in the loss of BRCA1.
3. We also identified that downregulation of AKT diminished the breast tumor formation in Brca1-deficient mouse model.
Ⅳ.Further Plan
1. Although BRCA1-deficient breast cancer showed the high incidence in tumor formation, there is no adequate treatment and prevention way. This study hypothesized that obesity and estrogen are important factors for tumorigenesis.
2. Thus, this study will provide the importance of these factor for tumor formation by molecular analysis and will identify the target molecule in this process.
3. This study will also show the scientific explanation why loss of BRCA1 leads the tumor formation in majority of female population but not in male.
4. The mice model in this study will be helpful in similar study and will be used in developing of prevention and curative.