Role of the EglN2 Target FOXO3a in Breast Cancer

描述（由申请人提供）：八分之一的女性在其一生中会患乳腺癌。约70%的乳腺癌依赖于雌激素的存在而生长，分为雌激素受体（ER）阳性和雌激素依赖性。内质网调节多种基因的表达，Cyclin D1就是其中之一。我们最近的研究报道了雌激素诱导基因EglN2正调控Cyclin D1并参与乳腺肿瘤的发生。EglN2对Cyclin D1的调控很大程度上依赖于EglN2脯氨酸羟化酶活性。然而，EglN2调控Cyclin D1的机制在很大程度上仍然未知。为了鉴定介导这一过程的潜在EglN2脯氨酸羟化酶底物，我对EglN2底物进行了体外羟化筛选。FOXO3a被确定为潜在的EglN2靶点。我计划验证FOXO3a是一种新的EglN2底物（Aim 1），并在体外和体内研究FOXO3a是否介导EglN2对Cyclin D1和乳腺癌细胞增殖的影响（Aim 2）。最后，我将系统地寻找egln2介导的乳腺肿瘤发生中的FOXO3a直接转录靶点（目的3）。本研究将阐明EglN2介导乳腺肿瘤发生的机制以及FOXO3a在这一过程中的重要作用。

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.