Role of EgIN2 Prolyl Hydroxylase in Mammary Tumorigenesis

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。在超过50%的乳腺癌中观察到高水平的细胞周期蛋白D1。Cyclin D1表达下调可抑制体内乳腺肿瘤的生长。另一个ER靶点，EglN2Pro羟基酶，被发现调节Cyclin D1的表达，它将ER放在EglN2的上游，EglN2放在Cyclin D1的上游。在这项提案中，我计划使用遗传学和生化方法的组合来了解EglN2在ER信号转导和乳腺肿瘤发生中的作用。首先，我将确定EglN2的缺失是否会抑制乳腺上皮细胞的体外转化。接下来，我将把我发现在体外可以减缓乳腺癌生长的EglN2下调的乳腺癌细胞引入小鼠体内，以测试它们是否会减缓体内肿瘤的生长。最后，我将研究EglN2调节Cyclin D1表达的机制。总之，这些拟议的研究描述了一种下调Cyclin D1的创新方法。公共卫生相关性：收集的数据将极大地丰富我们对EglN2在雌激素受体(ER)信号转导和乳腺肿瘤发生中的作用的理解。因此，它将有助于开发有效靶向ER下游信号通路的药物，并为乳腺癌的治疗提供一种新的、潜在的成功治疗策略。

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. High levels of Cyclin D1 have been observed in over 50% of mammary carcinomas. Downregulation of Cyclin D1 could inhibit breast tumor growth in vivo. Another ER target, EglN2 prolyl hydroxylase, has been found to regulate the expression of Cyclin D1, which places ER upstream of EglN2, and EglN2 upstream of Cyclin D1. In this proposal, I plan to use a combination of genetic and biochemical approaches to understand the role of EglN2 in ER signaling and mammary tumorigenesis. First, I will determine whether EglN2 loss will inhibit breast epithelia cell transformation in vitro. Next, I will introduce EglN2-downregulated breast cancer cells, which I found to slow breast cancer growth in vitro, into mice to test whether they slow down tumor growth in vivo. Lastly, I will study the mechanism by which EglN2 regulates Cyclin D1 expression. Together, these proposed studies describe an innovative way to downregulate Cyclin D1. PUBLIC HEALTH RELEVANCE: The data collected will greatly enrich our understanding of the role of EglN2 in Estrogen Receptor (ER) signaling and mammary tumorigenesis. Therefore, it will facilitate the development of effective drug targeting ER downstream signaling and provide a novel and potential successful therapeutic strategy for breast cancer treatment.