Role of the EglN2 Target FOXO3a in Breast Cancer

摘要： 每八名女性中就有一名会在一生中罹患乳腺癌。大约70%的乳腺癌患者 在雌激素的存在下生长，并分为雌激素受体(ER)阳性和雌激素 依附的。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 据报道，雌激素诱导基因EglN2正向调节Cyclin D1，对乳房有促进作用 肿瘤发生学。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。按顺序 为了确定介导这一过程的潜在的EglN2Pro羟基酶底物，我在体外进行了 EglN底物的羟基化筛选。FOXO3a被确定为潜在的EglN2靶标。我计划这样做 验证FOXO3a作为新的EglN底物(目标1)，并检查FOXO3a是否介导了 EglN_2对Cyclin D_1、乳腺癌细胞体外和体内增殖的影响(目的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)。建议数 研究将阐明EglN介导乳腺肿瘤发生的机制以及EglN在乳腺癌发生中的重要作用 FOXO3a在这一过程中。

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.