Role of the EglN2 Target FOXO3a in Breast Cancer

EglN2 靶点 FOXO3a 在乳腺癌中的作用

• 批准号: 8639747
• 负责人: Qing Zhang
• 金额: $ 23.41万
• 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/8639747
• 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： 八分之一的妇女一生将遭受乳腺癌。约70％的乳腺癌取决于 关于雌激素生长的存在，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，其中是细胞周期蛋白D1。我们最近的研究 报道说，雌激素诱导基因EGLN2积极调节细胞周期蛋白D1并有助于乳腺癌 肿瘤发生。 EGLN2对细胞周期蛋白D1的调节在很大程度上取决于EGLN2脯氨酰羟化酶活性。 然而，EGLN2调节Cyclin D1的基础机制仍然很大未知。为了 为了鉴定介导该过程的潜在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被确定为潜在的EGLN2目标。我打算 验证FOXO3A是一种新型的EGLN2底物（AIM 1），并检查FoxO3A是否介导 EGLN2在细胞周期蛋白D1上，体外和体内乳腺癌细胞增殖（AIM 2）。最后，我将系统地 在EGLN2介导的乳腺肿瘤发生中搜索FOXO3A直接转录靶标（AIM 3）。提议 研究将阐明EGLN2介导乳腺肿瘤发生的机制和 在此过程中FOXO3A。