PTEN蛋白失活是乳腺癌发生、发展及化疗耐药产生的重要机制。Nedd4-1是新近发现的调控PTEN特异性泛素化的E3连接酶，可在衔接蛋白Ndfip1介导下导致PTEN亚细胞定位异常促进其泛素化降解，但在乳腺癌的发生和化疗耐药的关系未见报道。我们前期实验显示， Ndfip1/Nedd4-1在乳腺癌化疗耐药组肿瘤细胞及多药耐药细胞系MCF-7/ADM中表达显著升高，而核PTEN表达缺失。由此我们提出：Ndfip1/Nedd4-1可促进PTEN的泛素化从而改变其亚细胞定位可能促进乳腺癌的发生发展和化疗耐药。为此，本课题拟以细胞模型转染Ndfip1/Nedd4-1表达质粒和iRNA质粒，研究其对PTEN的泛素化影响及细胞生长和多药耐药逆转情况，并在动物模型和临床病理标本中验证，并深入研究Ndfip1/Nedd4-1促进PTEN的泛素化影响耐药的分子机制，有助于为临床逆转乳腺癌多药耐药提供新靶点。

Breast cancer is the most common malignancy in women and chemoresistance is a major reason for failure of chemotherapy-based treatment. Inactivation of PTEN is an important mechanism involving in chemotherapy resistance development of breast cancer. The loss of PTEN protein in breast cancer is 33% ~ 50%, the protein post-translational modification may be the main reason leading to its inactivation, but the mechanism is not clear. Recently, nuclear PTEN plays a more important role in chromosome stability, DNA repair, cell cycle arrest and cellular apoptosis. PTEN enters the nucleus by several mechanisms including monoubiquitylation-dependent import. However, cytoplasmic PTEN is instability and may be degradation easily by poly ubiquitination. .NEDD4-1 is a proto-oncogenic Ubiquitin E3 ligase regulates PTEN activity by ubiquitination. The newly discovered Ndfip1 (Nedd4 family–interacting protein 1), an adaptor protein for the Nedd4 family of ubiquitin ligases, can bind the WW domain of Nedd4-1 by its PY motif which is also necessary for uniquitination of pten. Recent studies have found that Ndfip1-mediated ubiquitination of PTEN can lead to either monoubiquitination promoting nuclear accumulation or polyubiquitination promoting PTEN degradation in the cytoplasm. However, there is no related research on development and resistance effect of Ndfip1/Nedd4-1/PTEN ubiquitin pathway in tumor especially in breast cancer. .Our previous studies showed that:.1. The expression of nuclear PTEN was observed to be down-regulated in human breast cancer cells.However,up-regulated Ndfip1 and Nedd4-1 were observed in tissues of non-responders to new neoadjuvant chemotherapy as compared to those of responders by immunohistochemistry. .2. The resistant MCF-7/ADM cells were observed to have a lower neclear PTEN and higher expression of p-Akt, Nedd4-1 and Ndfip1 than that of sensitive cells by western blot. PTEN and Akt inhibitor perifosine reversed MDR phenotype partially by downregulation of MDR-1 gene expression by the inhibition of PI3K/Akt/NF-κB pathway in the MCF-7/ADM cell line..3. Transfection of Nedd4-1 enhanced nuclear PTEN export and down-regulated PTEN expression..Taken together, our findings indicate that Ndfip1/Nedd4-1-PTEN pathway might be the main mechanism of drug resistance of breast cancer cells. And it may act as a promising therapeutic target for improvement of responsiveness to chemotherapy in breast cancer. However, the role of Ndfip1/Nedd4-1 in modulating proliferation and chemoresistance of breast cancer remains largely unexplored. In this study, we aimed to investigate the possible role of Ndfip1/Nedd4-1 in the development and chemoresistance of breast cancer cells using tissue microarray, confocal, immunoprecipitation and RNA interference technologies. This maybe helpful for finding an attractive target for reveral of chemoresistance of breast cancer and provide a theoretical basis for breast cancer treatment and reseach.