Targeting the COX-2 Pathway to Reduce Breast Cancer Mortality

描述（由申请人提供）： 乳腺癌每年在美国新诊断的妇女中超过20万人。乳腺癌的死亡率一般是由于转移的发生。环氧合酶-2（考克斯-2）在乳腺癌中高度表达，并有助于转移成功。选择性考克斯-2抑制剂限制乳腺肿瘤的生长和转移，然而，最近发现的心脏毒性与全球考克斯-2抑制促使我们采取一种新的方法来靶向考克斯-2途径。肿瘤中的主要考克斯-2产物是前列腺素E2（PGE 2），其通过与四种EP受体（EP 1 -4）中的每一种结合来介导生物学效应。我们已经证明，这些受体中的两个，EP 1和EP 4，在调节乳腺肿瘤转移中发挥相反的作用。药理学拮抗作用或EP 4的基因沉默降低了转移潜力;拮抗EP 1增加了传播。我们假设EP 1作为一种转移抑制因子，在可能发展为播散性疾病的女性中表达降低。此外，EP 1通过依赖于自然杀伤细胞的机制控制转移。我们将进行以下具体目标来检验这些假设：使用已知长期存活的早期乳腺癌标本的独特集合，我们将（1）确定EP 1表达与临床乳腺癌行为的关系。使用临床前模型，我们将（2）确定EP 1的功能意义，并确定自然杀伤细胞对EP 1功能的贡献。EP 1和其他G蛋白偶联受体可以介导细胞核以及质膜中的细胞效应。我们将（3）确定EP 1的细胞定位和功能。由于所有的EP受体结合相同的配体，改变一个受体的功能可能会对其他EP受体的功能产生不利影响。我们将（4）确定恢复保护性（EP 1）和促转移性（EP 4）受体平衡的策略。 对退伍军人医疗保健的潜在影响：乳腺癌的发病率随着年龄的增长而增加，由于退伍军人的平均年龄为58岁，乳腺癌将在未来几年影响大量退伍军人。目前的退伍军人人口约为2600万;其中，近20万女性退伍军人将被诊断患有乳腺癌。因此，降低转移性乳腺癌的死亡率将对退伍军人医疗保健产生重大的社会和经济影响。这些研究将为调节EP 1表达和功能以实现这一目标奠定基础。 公共卫生相关性： 拟定工作与VA患者护理使命的相关性。 每年有近20万美国人新诊断出乳腺癌。乳腺癌具有巨大的社会和卫生保健影响，并且由于人口老龄化，将变得越来越常见。鉴于退伍军人的平均年龄为58岁，乳腺癌将在未来几年内影响大量退伍军人。目前美国和波多黎各的退伍军人人口约为2600万;其中，近20万女性退伍军人将在其一生中被诊断患有乳腺癌。降低这种疾病的死亡率是一个重要的目标。 乳腺癌的死亡率一般是由于局部和远处扩散或转移的发生。我们的实验室已经确定了乳腺癌转移的几个决定因素。众所周知，环氧合酶-2（考克斯-2）在乳腺癌、结肠癌、前列腺癌和其他恶性肿瘤中高度表达，并与不良预后相关。最近对考克斯-2抑制剂心脏毒性的关注促使我们研究其他靶向治疗考克斯-2通路的方法。我们推断，通过考克斯-2产物PGE 2阻止下游信号传导也是有益的;然而，该假设仅得到部分证实。我们发现乳腺肿瘤表达所有四种已知的PGE受体（EP 1 -4），拮抗EP 4是有益的，而拮抗EP 1实际上促进转移。因此，EP 1受体似乎起着转移抑制剂的作用。我们将进一步研究这些关系，以确定如何恢复保护性和反保护性EP受体功能之间的平衡，以降低转移性乳腺癌的死亡率。

DESCRIPTION (provided by applicant): ABSTRACT Breast cancers are newly diagnosed in more than 200,000 American women annually. Breast cancer mortality is generally due to the occurrence of metastasis. The cyclooxygenase-2 enzyme (COX-2) is highly expressed in breast cancer and contributes to metastatic success. Selective COX-2 inhibitors limit breast tumor growth and metastasis, however, recently identified cardiac toxicities associated with global COX-2 inhibition prompted us to take a novel approach to target the COX-2 pathway. The chief COX-2 product in tumors is prostaglandin E2 (PGE2) which mediates biological effects by binding to each of four EP receptors (EP1-4). We have demonstrated that two of these receptors, EP1 and EP4, play opposing roles in modulating breast tumor metastasis. Pharmacologic antagonism or genetic silencing of EP4 reduces metastatic potential; antagonism of EP1 increases dissemination. We hypothesize that EP1 acts as a metastasis suppressor and that expression is decreased in women likely to develop disseminated disease. Furthermore, that EP1 controls metastasis by a mechanism dependent on Natural Killer cells. We will carry out the following Specific Objectives to test these hypotheses: Using a unique collection of early stage breast cancer specimens for which longterm survival is known we will (1) determine the relationship of EP1 expression to behavior in clinical breast cancer. Using a preclinical model, we will (2) determine the functional significance of EP1 and determine the contribution of Natural Killer cells to EP1 function. EP1 and other G-protein coupled receptors may mediate cellular effects in the nucleus as well as the plasma membrane. We will (3) identify the cellular location and function of EP1. Since all EP receptors bind the same ligand, altering the function of one receptor may adversely affect other EP receptor functions. We will (4) identify strategies to restore the balance of the protective (EP1) and the pro-metastatic (EP4) receptor. Potential Impact on Veterans Health Care: Breast cancer incidence increases with age and since the mean age of Veterans is 58, breast cancer will impact a significant number of Veterans in the coming years. The current Veteran population is approximately 26 million; of these, nearly 200,000 female Veterans will be diagnosed with breast cancer. Therefore, reduction in mortality from metastatic breast cancer would have a significant social and economic impact on Veterans Health Care. These studies will establish a rationale for modulating EP1 expression and function to achieve this goal. PUBLIC HEALTH RELEVANCE: Relevance of the proposed work to the VA patient care mission. Cancers of the breast are newly diagnosed in nearly 200,000 Americans each year. Breast cancer has an enormous societal and health care impact and, due to the aging population, will become increasingly common. Given that the mean age of Veterans is 58, breast cancer will impact a significant number of Veterans in the next few years. The current Veteran population in the U.S. and Puerto Rico is approximately 26 million; of these, nearly 200,000 female Veterans will be diagnosed with breast cancer during their lifetimes. Reduction in mortality from this disease is an important goal. Breast cancer mortality is generally due to the occurrence of local and distant spread or metastasis. Our laboratory has identified several determinants of breast cancer metastasis. It is well established that the cyclooxygenase-2 (COX-2) enzyme is highly expressed and is associated with a poor prognosis in breast, colon, prostate and other malignancies. Recent concerns regarding the cardiac toxicity of COX-2 inhibitors prompted us to examine other approaches to therapeutically target the COX-2 pathway. We reasoned that preventing downstream signaling through the COX-2 product PGE2 would also be beneficial; however that hypothesis was only partially confirmed. We showed that breast tumors express all four known PGE receptors (EP1-4) and that antagonizing EP4 is beneficial whereas antagonism of EP1 actually promotes metastasis. Thus, the EP1 receptor appears to function as a metastasis suppressor. We will examine these relationships further in order to identify how to restore the balance between protective and anti-protective EP receptor function to reduce mortality from metastatic breast cancer.