E3泛素连接酶是乳腺癌治疗新靶点。我们前期研究发现RNF126促进乳腺癌细胞周期和DNA损伤修复，高表达和不良预后、放疗及多个靶向药物敏感性相关，沉默RNF126表达抑制肿瘤生长。然而RNF126的生理功能和病理功能未在基因敲除小鼠模型得到验证和阐明。基于扎实的前期基础，我们假设：RNF126在体内通过促进端粒酶表达、DNA损伤修复、炎症和细胞周期在乳腺癌中发挥促癌作用，RNF126是一个乳腺癌治疗干预靶点，抑制RNF126酶活性的小分子化合物可以用于乳腺癌治疗。本研究我们首次利用构建的乳腺特异性敲除Rnf126的小鼠明确RNF126在乳腺癌发生发展和治疗中的作用，解析其作用的分子机制并建立高通量筛选系统筛选RNF126小分子抑制剂。研究结果将为进一步理解RNF126的生理病理功能和作用机制以及开发针对RNF126的靶向治疗奠定基础。

E3 ubiquitin ligases are novel therapeutic targets for breast cancer. Our previous studies suggest that RNF126 promotes breast cancer cell cycle progression through targeting p21 for ubiquitin-mediated degradation (Cancer Research 2013). Additionally, RNF126 promotes DNA damage repair through upregulating the expression of BRCA1 and CHK1. The RNF126 protein expression was elevated in breast cancer tissue samples. RNF126 was associated with a poor clinical outcome. RNF126 could serve as a biomarker to predict efficacy of radiotherapy, PARP inhibitors, and CHK1 inhibitors. However, the physiological and pathological roles of RNF126 in breast and breast cancer have not been studied. We hypothesize that RNF126 promotes breast cancer through regulating the expression of telomerase, DNA damage repair, inflammation and cell cycle，RNF126 is an effective therapeutic target, and the RNF126 inhibitors could be developed for breast cancer therapy. In this study, we propose to use Rnf126 breast specific knockout mouse model to verify the functions and mechanisms of RNF126 in breast cancer. Furthermore, we develop a high throughput screening platform to screen RNF126 small molecular inhibitors for breast cancer treatment. Completion of this project will reveal the physiological and pathological functions of RNF126 in vivo, determine the functional mechanism by which RNF126 promotes breast cancer, validate RNF126 as a therapeutic target, and develop small molecular compounds against RNF126 for breast cancer treatment.