从CRYL1基因甲基化探讨乳腺癌赫赛汀耐药的机制

Herceptin resistance is one of the factors leading to low survival rate of breast cancer patients. The project is based on the current research status of breast cancer resistance to herceptin. Combined with early study that the role of tumor suppressor gene CRYL1 in cancer, the loss expression and hypermethylation status of CRYL1 in herceptin resistant breast cancer cells ,we hypothesized that hypermethylation of CRYL1 may activate CRYL1/β-catenin/EGFR pathway and be involved in process of breast cancer resistance to herceptin.The project intends to firstly detect the expression level and methylation status of CRYL1 in herceptin resistant breast cancer tissues and cell lines, analysize the correlation of the expression level of CRYL1 and downstream gene with herceptin resistance phenotype of breast cancer.Then through up-regulating or inhibiting CRYL1 expression in breast cancer experimental model in vitro and in vivo ,taking CRYL1 as a starting point, we plan to investigate the biological characteristics changes of herceptin resistant /sensitive of breast cancer cells, further clarify the mechanism of CRYL1 methylation activation CRYL1/β-catenin/EGFR pathway under herceptin treatment environment, explore if CRYL1 methylation is one of the initiating factor maintaining herceptin resistance. The study will be helpful for understanding the mechanism of herceptin resistance, and laying a foundation for exploring more effective biological targeting therapy to breast cancer.

乳腺癌赫赛汀耐药是导致患者远期生存率低的因素之一。项目基于乳腺癌赫赛汀耐药研究的现状，结合先期抑癌基因CRYL1在肿瘤中作用,乳腺癌赫赛汀耐药细胞中CRYL1表达缺失并且甲基化状态升高，提出CRYL1基因甲基化可能激活CRYL1/β- catenin/EGFR通路，从而引起赫赛汀耐药。项目拟先通过检测赫赛汀耐药乳腺癌组织及细胞中CRYL1表达和甲基化状态，分析CRYL1及下游核心因子与赫赛汀耐药表型的相关性；再通过上调或抑制CRYL1的表达，以CRYL1为出发点，在体外体内实验模型中研究赫赛汀耐药/敏感细胞的生物学特性变化；并进一步阐明赫赛汀环境下，CRYL1甲基化通过激活CRYL1/β-catenin/EGFR信号通路，在维系乳腺癌对赫赛汀耐药生物学效应中的作用及机制。研究将有助于深入的了解赫赛汀耐药机制，为探索更有效的生物靶向治疗奠定一定的基础。

乳腺癌赫赛汀耐药是导致患者远期生存率低的因素之一。项目基于乳腺癌赫赛汀耐药研究的现状，结合先期抑癌基因CRYL1在肿瘤中作用,乳腺癌赫赛汀耐药细胞中CRYL1表达缺失并且甲基化状态升高，提出CRYL1基因甲基化可能激活CRYL1/β- catenin/EGFR通路，从而引起赫赛汀耐药。本项目拟在前期工作的基础上进行以下研究：1.项目拟先通过检测赫赛汀耐药乳腺癌组织及细胞中CRYL1表达和甲基化状态，分析CRYL1及下游核心因子与赫赛汀耐药表型的相关性；再通过上调或抑制CRYL1的表达，以CRYL1为出发点，在体外体内实验模型中研究赫赛汀耐药/敏感细胞的生物学特性变化, 并进一步阐明赫赛汀环境下，CRYL1甲基化通过激活CRYL1/β-catenin/EGFR信号通路，在维系乳腺癌对赫赛汀耐药生物学效应中的作用及机制；2.并且也发现了Livin基因在乳腺癌发生发展中的重要作用，证实了Livin通过AKT和EMT信号通路促进乳腺癌的发生发展；3.在近期实验中，发现在乳腺癌赫赛汀耐药细胞中Livin基因表达上调，并且通过ERK1/2和AKT信号通路介导乳腺癌赫赛汀耐药机制。研究将有助于深入的了解乳腺癌的发生发展机制，为探索更有效的生物靶向治疗奠定一定的基础。