유방암세포에서 간엽 형질 유지에 대한 Fyn의 역할

Abstract

EMT) 에 필요한 인자임을 밝혀냈다. 특히 FYN은 유방암 세포에서 NOTCH2의 발현을 증가뿐만 아니라, STAT5의 활성화를 통한 Jagged1 및 DLL4와 같은 NOTCH2 ligands의 발현 수준을 증가시켜 NOTCH2 신호 전달의 활성을 증진시키는 것을 밝혀냈다. FYN의 발현을 억제했을 때의 결과와 마찬가지로 STAT5 및 NOTCH2 신호 전달의 억제는 basal-type 유방암 세포의 이동 및 침윤 능력을 감소시켰다. 또한, 동물실험에서도 FYN을 표적으로 한 억제는 효과적으로 basal-type 유방암 세포의 전이를 억제하였고, 마우스의 생존률을 연장시키는 등 유방암 치료를 위한 임상적 적절성이 높음을 확인하였다.; Human breast cancer is a heterogeneous disease characterized by differences in pathology, molecular profiles, and responsiveness to treatment. Despite improvement of therapies for luminal type of breast cancers, the oncogenic drivers in basal type breast cancer cells are poorly understood and there is no effective treatment for this type of cancers. In the present work, I found that basal type breast cancer cells selectively express higher levels of Fyn among Src family proteins, compared to luminal type of breast cancer cells. By modulating the expression levels of Fyn in basal- or luminal-type of breast cancer cells, it was found that Fyn, among Src family kinases, is necessary and sufficient for epithelial-mesenchymal transition (EMT) in breast cancer cells. Notably, it was shown that Fyn increases expression levels of Notch ligands such as Jagged1 and DLL4 through activation of STAT5, thereby caused to increase Notch signaling in basal type of breast cancer cells. In agreement with these results, likely to down-regulation of Fyn, inhibition of STAT5 and Notch signaling decreased the migratory and invasive properties of basal type breast cancer cells. Also, in vivo, targeting of Fyn effectively inhibited the metastatic ability of basal type breast cancer cells and caused to extend the survival rate of mice, implicating its clinical relevance for therapies of basal type breast cancers.|유방암은 병리학적 차이, 분자적 프로파일 및 항암치료에 대한 차별적인 반응성 등이 관찰되는 복합적인 이종 질병이다. Luminal-type 유방암에 대한 치료의 개선에도 불구하고, 아직까지 basal-type의 유방암 치료에 대해서는 종양에서 유래된 분자적 메커니즘과 신호기전에 대한 많은 이해와 연구가 필요한 실정이다. 본 연구에서는Src kinase family (SFKs) 중 하나인 FYN의 발현이luminal-type의 유방암 세포에 비해 basal-type의 유방암 세포에서 높게 나타남을 확인하고 FYN이 유방암 세포의 상피-간엽성 전환 (Epithelial-Mesenchymal Transition; Human breast cancer is a heterogeneous disease characterized by differences in pathology, molecular profiles, and responsiveness to treatment. Despite improvement of therapies for luminal type of breast cancers, the oncogenic drivers in basal type breast cancer cells are poorly understood and there is no effective treatment for this type of cancers. In the present work, I found that basal type breast cancer cells selectively express higher levels of Fyn among Src family proteins, compared to luminal type of breast cancer cells. By modulating the expression levels of Fyn in basal- or luminal-type of breast cancer cells, it was found that Fyn, among Src family kinases, is necessary and sufficient for epithelial-mesenchymal transition (EMT) in breast cancer cells. Notably, it was shown that Fyn increases expression levels of Notch ligands such as Jagged1 and DLL4 through activation of STAT5, thereby caused to increase Notch signaling in basal type of breast cancer cells. In agreement with these results, likely to down-regulation of Fyn, inhibition of STAT5 and Notch signaling decreased the migratory and invasive properties of basal type breast cancer cells. Also, in vivo, targeting of Fyn effectively inhibited the metastatic ability of basal type breast cancer cells and caused to extend the survival rate of mice, implicating its clinical relevance for therapies of basal type breast cancers.