人源蛋白酪氨酸磷酸酶PTPN12的结构与功能研究

项目名称： 人源蛋白酪氨酸磷酸酶PTPN12的结构与功能研究

项目编号： No.31300601

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 董辉

作者单位： 中国医学科学院

项目金额： 22万元

中文摘要： 乳腺癌是严重危害女性健康的常见恶性肿瘤之一。根据激素受体和人表皮生长因子HER2的表达模式，乳腺癌可分为luminal型、HER2过表达型和三阴型三种主要肿瘤亚型。其中"三阴型乳腺癌"特指雌激素受体、孕激素受体及HER2表达缺失的乳腺癌表型。该表型乳腺癌肿瘤侵袭性强，内脏转移、脑转移机率较高，短期内易复发，5年生存率不足15%。最新的研究结果表明，蛋白酪氨酸磷酸酶PTPN12在多种三阴型乳腺癌细胞系存在功能缺失性基因突变，PTPN12缺失导致HER2/EGFR和其他RTK信号通路被异常激活。因此，PTPN12是三阴型乳腺癌发生的关键性肿瘤抑制因子和潜在的癌症治疗靶点。本课题主要通过PTPN12的结构解析、体外生化功能与体内细胞学实验、荷瘤动物模型及人体肿瘤标本研究，探索PTPN12与肿瘤生长、转移的关系，为针对PTPN12的药物开发提供详细的结构信息。

中文关键词： 酪氨酸磷酸酶；结构；功能；乳腺癌；信号传导

英文摘要： Breast cancer is the most common malignancy among women and is comprised of a heterogeneous group of diseases divided into three major subtypes based on the pattern of expression of hormone receptors and human epidermal growth factor receptor-2 (HER2): luminal tumors, HER2 amplified tumors, and triple-negative breast cancer (TNBC). TNBC subtype is distinguished by negative immunohistochemical assays for expression of the estrogen and progesterone receptors (ER/PR) and HER2. Patients with TNBC generally experience a more aggressive clinical course with increased risk of disease progression and poorer overall survival. Lack of effective targeted agents and the aggressive natural history of TNBC result in the fact that less than 15% of all patients can last for five years. Protein tyrosine phosphatase 12 (PTPN12) function is frequently compromised in TNBC by deletions, defective sequence variants, or loss of expression. Restoring PTPN12 expression in PTPN12 deficient TNBC cells inhibits their proliferation, tumorigenicity, and metastatic potential in vivo, suggesting that PTPN12 is a commonly inactivated tumor suppressor and, therefore, a target for cancer therapies. In this study, we focus on the structural and functional features of PTPN12, providing insight into its distinct substrate specificity in cancer cells

英文关键词： tyrosine phosphatase；structure；function；breast cancer；signal transduction