Role of Cdc25A in breast cancer

描述(申请人提供)：CDC25家族双特异性蛋白磷酸酶通过去磷酸化细胞周期蛋白依赖性蛋白激酶(CDKs)的三磷酸腺苷结合域来激活CDKs，作为真核细胞周期进程的限速调节器。作为对DNA损伤的响应，CDC25磷酸酶通过依赖CHK1/2的磷酸化失活，形成细胞周期检查点的关键靶点。在哺乳动物的三种CDC25蛋白中，CDC25A似乎在细胞周期的发育和检查点控制中发挥着独特而不可或缺的作用，而CDC25B和CDC25C在发育和检查点中的功能似乎更多地重叠或不必要。CDC25A在包括乳腺癌在内的多种人类癌症组织中过表达，但通常不会观察到CDC25A基因与癌症相关的扩增。这一持续研究计划的长期目标是了解CDC25A在乳腺癌中的确切作用，并为针对该蛋白的抗癌治疗奠定科学基础。以往的研究表明，CDC25A在早期乳腺癌人群中的过度表达与雌激素和孕激素受体阴性表达、P53突变、肿瘤分级高和患者预后不良有关。目前评估的中心假说是P53失活和CDC25A表达失控通过正反馈机制相互促进，这两个事件在功能上协同作用，在肿瘤启动过程中建立染色体不稳定性，并加剧恶性表型，特别是在三阴性乳腺癌中。在新的研究计划中，将追求三个具体目标：(1)确定非调控CDC25A表达与P53失活在乳腺癌发生发展中的协同作用；(2)确定非调控CDC25A表达乳腺上皮细胞中染色体不稳定的机制和意义；(3)确定CDC25A与P53依赖的检查点和细胞凋亡在乳腺肿瘤发生过程中的体内相互作用。这些研究应该为CDC25A的致癌作用提供重要的见解，CDC25A现在被视为治疗靶点。

DESCRIPTION (provided by applicant): CDC25 family dual-specific protein phosphatases activate cyclin-dependent kinases (CDKs) by dephosphorylation of the ATP binding domains of the kinases, functioning as rate-limiting regulators of eukaryotic cell cycle progression. In response to DNA damages, CDC25 phosphatases are inactivated by CHK1/2-dependent phosphorylation, forming critical targets of cell cycle checkpoint. Of mammalian three CDC25 proteins, CDC25A appears to play a distinct and indispensable role in developmental and checkpoint control of the cell cycle, while the functions of CDC25B and CDC25C in development and checkpoint appear more overlapping or dispensable. CDC25A is overexpressed in a variety of human cancer tissues, including breast cancer, although cancer-associated amplification of the CDC25A locus is not usually observed. The long-term goal of this continued research program is to understand the exact role of CDC25A in breast cancer and establish a scientific basis for anti-cancer therapies targeted on this protein. Previous studies indicate that CDC25A overexpression, which is observed in a population of early stage breast cancers, correlates with negative expression of estrogen and progesterone receptors, p53 mutations, high tumor grades and poor prognosis of patients. The central hypothesis evaluated in the present application is that p53 inactivation and deregulated CDC25A expression promote each other with a positive feedback mechanism, and both events functionally cooperate in establishing chromosome instability during tumor initiation and exacerbating malignant phenotypes, especially in triple-negative breast cancer. In the renewed research program, three specific aims will be pursued: (1) Determine how deregulated CDC25A expression cooperates with p53 inactivation in the development of breast cancer; (2) Determine the mechanisms and significance of chromosome instability in mammary epithelial cells with deregulated CDC25A expression; (3) Define in vivo interactions of CDC25A with p53-dependent checkpoint and apoptosis during mammary tumorigenesis. These studies should provide significant insight into the oncogenic roles of CDC25A, which is now regarded as a therapeutic target.