Role of Cdc25A in breast cancer

描述（由申请人提供）：CDC 25家族双特异性蛋白磷酸酶通过激酶ATP结合结构域的去磷酸化激活细胞周期蛋白依赖性激酶（CDK），作为真核细胞周期进程的限速调节剂发挥作用。响应于DNA损伤，CDC 25磷酸酶通过CHK 1/2依赖性磷酸化而失活，形成细胞周期检查点的关键靶标。在哺乳动物的三种CDC 25蛋白中，CDC 25 A似乎在细胞周期的发育和检查点控制中发挥独特且不可或缺的作用，而CDC 25 B和CDC 25 C在发育和检查点中的功能似乎更加重叠或重叠。CDC 25 A在多种人类癌症组织中过表达，包括乳腺癌，尽管通常不会观察到CDC 25 A基因座的癌症相关扩增。这项持续研究计划的长期目标是了解CDC 25 A在乳腺癌中的确切作用，并为针对这种蛋白质的抗癌疗法建立科学基础。先前的研究表明，在早期乳腺癌人群中观察到的CDC 25 A过表达与雌激素和孕激素受体的阴性表达、p53突变、高肿瘤分级和患者预后不良相关。在本申请中评估的中心假设是p53失活和失调的CDC 25 A表达通过正反馈机制相互促进，并且这两个事件在肿瘤起始期间在建立染色体不稳定性和恶化恶性表型（特别是在三阴性乳腺癌中）中功能性地协作。在新的研究计划中，将有三个具体的目标：（1）确定在乳腺癌的发展中，CDC 25 A表达失调与p53失活的协同作用;（2）确定乳腺上皮细胞中CDC 25 A表达失调的染色体不稳定性的机制和意义;（3）明确乳腺肿瘤发生过程中CDC 25 A与p53依赖性检查点和细胞凋亡的体内相互作用。这些研究应该为CDC 25 A的致癌作用提供重要的见解，CDC 25 A现在被认为是治疗靶点。

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.