Role of the EglN2 Target FOXO3a in Breast Cancer

EglN2 靶点 FOXO3a 在乳腺癌中的作用

• 批准号: 8681385
• 负责人: Qing Zhang
• 金额: $ 24.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681385
• 关键词: Binding; Biological Models; Breast; Breast Cancer Cell; Cell Proliferation; Cells; ChIP-seq; Complex; Cyclin D1; Cyclins; Data; Development; Diagnosis; Down-Regulation; Estrogen Receptors; Estrogen receptor positive; Estrogens; Generations; Genes; Genetic Transcription; Hydroxylation; Immunoglobulin G; In Vitro; Knowledge; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mass Spectrum Analysis; Mediating; Microarray Analysis; Modality; Molecular; Process; Procollagen-Proline Dioxygenase; Proteins; RNA; Regulation; Reporting; Research; Role; Site; Small Interfering RNA; Woman; breast tumorigenesis; cancer microarray; cancer therapy; cancer type; fitness; in vivo; in vivo Model; inhibitor/antagonist; malignant breast neoplasm; novel; overexpression; research study; screening; small hairpin RNA; tumor; tumor growth; tumor progression; ubiquitin-protein ligase

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.

概括： 八分之一的女性一生中会患乳腺癌。大约70%的乳腺癌取决于 雌激素的存在才能生长，被分类为雌激素受体（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 报道雌激素诱导基因EglN2正向调控Cyclin D1，有助于乳腺发育 肿瘤发生。 EglN2 对 Cyclin D1 的调节很大程度上取决于 EglN2 脯氨酰羟化酶活性。 然而，EglN2 调节 Cyclin D1 的机制仍然很大程度上未知。为了 为了确定介导这一过程的潜在 EglN2 脯氨酰羟化酶底物，我在体外进行了实验 EglN2 底物的羟基化筛选。 FOXO3a 被确定为潜在的 EglN2 靶标。我计划 验证 FOXO3a 作为一种新型 EglN2 底物（目标 1）并检查 FOXO3a 是否介导 EglN2 对 Cyclin D1 的影响，体外和体内乳腺癌细胞增殖（目标 2）。最后我会系统地 寻找 EglN2 介导的乳腺肿瘤发生中的 FOXO3a 直接转录靶标（目标 3）。拟议的 研究将阐明EglN2介导乳腺肿瘤发生的机制以及其重要作用 FOXO3a在此过程中。