Role of the EglN2 Target FOXO3a in Breast Cancer

总结： 八分之一的女性在一生中会患乳腺癌。大约70%的乳腺癌 在雌激素的存在下生长，并被归类为雌激素受体（ER）阳性和雌激素 依赖。ER调节许多基因的表达，其中包括Cyclin D1。我们最近的研究 EglN2是一种雌激素诱导基因，它能积极调节细胞周期蛋白D1，并有助于乳腺癌的发生。 肿瘤发生EglN2对Cyclin D1的调控主要依赖于其脯氨酰羟化酶活性。 然而，EglN2调节Cyclin D1的机制在很大程度上仍然未知。为了 为了鉴定介导这一过程的潜在的EglN2脯氨酰羟化酶底物，我在体外进行了 EglN2底物的羟基化筛选。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、乳腺癌细胞增殖的体外和体内作用（目的2）。最后，我将系统地 在EglN2介导的乳腺肿瘤发生中寻找FOXO 3a直接转录靶点（Aim 3）。拟议 研究将阐明EglN2介导乳腺肿瘤发生的机制以及EglN2在乳腺癌发生中的重要作用。 FOXO3a在这个过程中。

SUMMARY: 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 depend 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.