Novel effectors of ERK signaling and their potential roles in the treatment of en

子宫内膜癌是女性生殖道最常见的恶性肿瘤。大多数子宫内膜 癌症是在早期发现的，并伴有绝经后出血。这些患者最初 采用综合手术分期治疗。这种治疗通常是诊断疾病的程度， 有治疗作用的然而，子宫癌患者管理的一个关键临床问题是如何 最好的早期诊断和侵袭性病理组织型， mortality. 患有高阶段或复发性癌症的患者患有需要新治疗的全身性疾病 干预措施。有效的治疗方法在很大程度上缺乏。更好地了解癌症生物学，例如 信号转导通路，将导致新的治疗策略，将提高这些生存 患者有丝分裂原激活途径激酶信号传导途径的激活实质上有助于 子宫内膜肿瘤发生我们的小组已经通过三部分鉴定了30种新型ERK底物， 功能基因组学方法在C. elegans模型这些蛋白质的人类直向同源物表达于 子宫内膜癌细胞系是候选ERK底物。到目前为止，在研究的候选人中，我们显示 GSK 3 n对多种子宫内膜癌细胞系的细胞生长很重要， 治疗干预措施。在这项提案中，我们将继续表征新的ERK候选底物 子宫内膜癌在目标1中，我们将评估候选ERK 1/2底物在正常人中的表达。 子宫内膜、原发性子宫内膜癌和子宫内膜癌细胞系，并确定底物 磷酸化是ERK依赖性的。然后在目标2中，我们将确定ERK底物与细胞凋亡的关系。 磷酸化状态和上游ERK信号通路激活， ERK底物表达的临床病理意义。最后，在目标3中，我们将探索GSKSD 抑制作为子宫内膜癌的潜在疗法，并评估抑制其他ERK底物的作用 在子宫内膜癌细胞系中起作用。这些研究应能更好地了解 ERK通路在子宫内膜癌发生中的作用，并可能导致改善临床生物学特性。 治疗 相关性（参见说明）： 这项工作的提出将导致双方的子宫内膜癌生物学和新的理解 检测、预防和治疗子宫癌的方法， 发病率和死亡率。

Endometrial carinoma is the most common cancer of the female reproductive tract. Most endometrial cancers are found at an early stage and present with postmenopausal bleeding. These patients are initially treated with comprehensive surgical staging. This treatment is often diagnostic ofthe extent of disease and therapeutic. However, a key clinical problem in the management of patients with uterine cancers is how to best fre¿t~ab\r¿rhced'stagieclisease ahdlhe aggressive pathoTogic histotypes that account for signficant mortality. Patients with high stage or recurrent cancers have systemic disease requiring novel therapeutic interventions. Effective therapies are largely lacking. A better understanding ofthe cancer biology, such as signal transduction pathways, will lead to new treatment strategies that will improve the survival of these patients. Activation of the Mitogen Activating Pathway Kinase signaling pathway contributes substantially to endometrial tumorigenesis. Our group has identified thirty novel ERK substrates through a three-part functional genomic approach in the C. elegans model. The human orthologs of these proteins expressed in endometrial cancer cell lines are candidate ERK substrates. Thus far, of the candidates studied, we showed that GSK3n is important to cell growth in multiple endometrial cancer cell lines and has potential for therapeutic interventions.. In this proposal, we will continue to characterize novel ERK candidate substrates in endometrial cancer. In Aim 1, we will assess expression of candidate ERK1/2 substrates in the normal endometrium, primary endometrial cancers and endometrial cancer cell lines and determine if substrate phosphorylation is ERK-dependent. Then in aim 2, we will determine the relationship between ERK substrate phosphorylation status and upstream ERK signaling pathway activation in primary endometrial cancers and clinicopathologic significance of ERK substrate expression. Finally in aim 3, we will explore GSKSD inhibition as potential therapy for endometrial cancer and assess the role of inhibiting other ERK substrates plays in endometrial cancer cell lines. Together these studies should provide a better understanding of the role the ERK pathway plays in endometrial carcinogenesis and may lead to improved clinical biological therapies. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.