Role of the EglN2 Target FOXO3a in Breast Cancer

描述(申请人提供)：每八名女性中就有一人会在一生中罹患乳腺癌。大约70%的乳腺癌依赖于雌激素的存在而生长，被归类为雌激素受体(ER)阳性和雌激素依赖。内质网调控多种基因的表达，Cyclin D1就是其中之一。我们最近的研究报道，雌激素诱导基因EglN2正向调节Cyclin D1，参与乳腺肿瘤的发生。EglN_2对Cyclin D_1的调控在很大程度上依赖于EglN_2脯氨酸羟基酶的活性。然而，EglN2对Cyclin D1的调控机制目前仍不清楚。为了确定介导这一过程的潜在的EglN2Pro羟基酶底物，我对EglN2底物进行了体外羟化筛选。FOXO3a被确定为潜在的EglN2靶标。我计划验证FOXO3a作为一种新的EglN2底物(Aim 1)，并研究FOXO3a是否介导EglN2对Cyclin D1的影响，以及乳腺癌细胞的体外和体内增殖(Aim 2)。最后，我将系统地寻找FOXO3a在EglN2介导的乳腺肿瘤发生中的直接转录靶点(目标3)。这项拟议的研究将阐明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。 公共卫生相关性：我们开发针对乳腺癌的靶向治疗的能力在很大程度上取决于通过生成和检查准确的体外和体内模型系统，更详细地了解EglN2相关乳腺肿瘤发生的分子机制。这项建议将研究FOXO3a作为缺失的一环的作用，EglN2通过它来调节Cyclin D1和乳腺肿瘤的发生。这项提案的成功完成将推动EglN2特异性抑制剂的开发，作为一种诱导FOXO3a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.