Role of the EglN2 Target FOXO3a in Breast Cancer

描述（由申请人提供）：八分之一的女性一生中会患有乳腺癌。大约70%的乳腺癌依赖于雌激素的存在而生长，并被分类为雌激素受体（ER）阳性和雌激素依赖性。ER调节许多基因的表达，其中包括Cyclin D1。我们最近的研究报道EglN2是一种雌激素诱导基因，它正调控Cyclin D1，并参与乳腺肿瘤的发生。EglN2对细胞周期蛋白D1的调节在很大程度上依赖于EglN2脯氨酰羟化酶活性。然而，EglN2调节Cyclin D1的机制在很大程度上仍然未知。为了鉴定介导该过程的潜在EglN2脯氨酰羟化酶底物，我对EglN2底物进行了体外羟基化筛选。FOXO3a被鉴定为潜在的EglN2靶标。我计划验证FOXO3a作为一种新的EglN2底物（目的1），并检查FOXO3a是否介导EglN2对细胞周期蛋白D1的影响，体外和体内乳腺癌细胞增殖（目的2）。最后，我将系统地寻找FOXO 3a在EglN2介导的乳腺肿瘤发生中的直接转录靶点（目的3）。该研究将阐明EglN2介导乳腺肿瘤发生的机制以及FOXO 3a在此过程中的重要作用。 公共卫生相关性：我们开发针对乳腺癌的靶向疗法的能力在很大程度上依赖于通过生成和检查准确的体外和体内模型系统对EglN2相关的乳腺肿瘤发生的分子机制的更详细的理解。该提案将研究FOXO 3a作为EglN2调节Cyclin D1和乳腺肿瘤发生的缺失环节的作用。该提案的成功完成将促进EglN2特异性抑制剂的开发，作为诱导FOXO 3a治疗癌症（包括乳腺癌）的手段。

DESCRIPTION (provided by applicant): One in eight women will suffer breast cancer during their lifetime. About 70% of breast cancer depends on the presence of estrogen to grow, and is classified as Estrogen Receptor (ER) positive and estrogen dependent. ER regulates the expression of many genes, among which is Cyclin D1. Our recently research reported that EglN2, an estrogen inducible gene, positively regulates Cyclin D1 and contributes to breast tumorigenesis. The regulation of Cyclin D1 by EglN2 is largely dependent on EglN2 prolyl hydroxylase activity. However, the mechanism underlying the regulation of Cyclin D1 by EglN2 remains largely unknown. In order to identify the potential EglN2 prolyl hydroxylase substrates that mediate this process, I performed in vitro hydroxylation screening for EglN2 substrates. FOXO3a was identified as a potential EglN2 target. I plan to validate FOXO3a as a novel EglN2 substrate (Aim 1) and examine whether FOXO3a mediates the effect of EglN2 on Cyclin D1, breast cancer cell proliferation in vitro and in vivo (Aim 2). Lastly, I will systematically search for FOXO3a direct transcription targets in EglN2-mediated breast tumorigenesis (Aim 3). The proposed research will elucidate the mechanism by which EglN2 mediates breast tumorigenesis and the important role of FOXO3a in this process. PUBLIC HEALTH RELEVANCE: Our ability to develop targeted therapies against breast cancer is heavily dependent on a more detailed understanding of the molecular mechanism of EglN2-related breast tumorigenesis through generation and examination of accurate in vitro and in vivo model systems. This proposal will study the role of FOXO3a as the missing link by which EglN2 regulates Cyclin D1 and breast tumorigenesis. Successful completion of this proposal will motivate the development of EglN2 specific inhibitors as a means to induce FOXO3a to treat cancers, including breast cancers.