BRCA1抑癌蛋白在维护基因组稳定性、抑制乳腺癌发生中发挥关键作用。BRCA1蛋白质稳态的平衡和维持对于其生物学功能的行使至关重要，BRCA1突变或缺失引起的BRCA1分子功能不足（Haploinsufficiency）或丧失是导致乳腺癌和卵巢癌等疾病的重要因素。正常细胞内BRCA1的蛋白质水平受到严格调控，其中泛素-蛋白酶体降解途径是调控BRCA1蛋白质稳态平衡的重要机制，但是参与靶向BRCA1的核心因子并不清楚。近期我们研究发现，DCAF8是重要的BRCA1调控因子，它可以与Cullin4形成E3酶复合物，介导对BRCA1的泛素化修饰和蛋白酶体降解。本项目拟在前期工作基础上，深入研究DCAF8调控 BRCA1蛋白质稳态的分子机制；探索其在正常乳腺发育和分化中的作用，以及其异常表达与乳腺癌发生的关系。该研究对于揭示细胞BRCA1蛋白质稳态的调控机制、揭示乳腺癌发生的分子机理具有重要意义。

BRCA1 is an important tumor suppressor, playing critical roles in the maintenance of genomic stability and suppression of breast cancer. The balance and maintenance of BRCA1 protein homeostasis is crucial for the execution of its cellular functions. Mutation of BRCA1 can cause decrease/loss of BRCA1 protein, leading to haploinsufficiency or loss of BRCA1 function, which is thought to be a main cause for breast/ovarian carcinogenesis. Under physiological conditions, cellular level of BRCA1 protein is tightly regulated. The ubiquitin-proteasome system (UPS) pathway plays essential role in degrading BRCA1 protein and is considered as the most important mechanism for regulation of BRCA1 protein homeostasis, however, core factors that are involved in this pathway has not yet been identified. Recently we have identified DCAF8 as a key regulator for BRCA1. DCAF8 could play essential role in the ubiquitination and subsequent degradation of BRCA1. Alteration in DCAF8 expression could lead to loss of BRCA1 protein homeostasis, and may be associated with breast tumorigenesis. Based on our recent findings, we will aim to i) investigate the mechanism by which CRL4-DCAF8 regulate BRCA1 homeostasis; ii) investigate the role of DCAF8 in the development and differentiation of mammary gland; iii) explore the association of alteration and pathogenesis of breast cancer. This study will elucidate the mechanism for BRCA1 protein homeostasis and for breast carcinogenesis, and will have important implications in the prevention, treatment of breast cancer as well as in the development of novel antitumor drugs.