Targeting the COX-2 Pathway to Reduce Breast Cancer Mortality

针对 COX-2 通路降低乳腺癌死亡率

• 批准号: 7682641
• 负责人: Amy M. Fulton
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682641
• 关键词: Affect; African American; Age; Aggressive behavior; Aging; American; Apoptosis; Behavior; Binding; Biological; Biology; Breast; Breast Adenocarcinoma; Cardiotoxicity; Cell Nucleus; Cell membrane; Chronic; Clinical; Collection; Colon; Complex; Coupled; Cyclooxygenase Inhibitors; Data; Death Rate; Diagnosis; Dinoprostone; Disease; Disease Progression; Distant; EP4 receptor; Effector Cell; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epidemiologic Studies; Equilibrium; European; Female; G-Protein-Coupled Receptors; Gene Expression Profile; Genetic; Goals; Health Services Accessibility; Healthcare; Immune; Incidence; Laboratories; Ligands; Location; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastasis Suppressor Genes; Metastatic to; Mission; Modeling; Mus; Natural Killer Cells; Neoplasm Metastasis; Newly Diagnosed; Outcome; Patient Care; Pattern; Play; Population; Pre-Clinical Model; Prostaglandin E Receptor; Prostate; Puerto Rico; Risk; Role; Signal Pathway; Signal Transduction; Social Impacts; Solid; Specimen; Staging; Stream; T-Lymphocyte; Testing; Therapeutic Intervention; Tumor Angiogenesis; Up-Regulation; Veterans; Woman; Work; aging population; cancer health disparity; cyclooxygenase 2; economic impact; enzyme activity; enzyme pathway; human WFDC2 protein; improved; malignant breast neoplasm; mortality; neoplastic cell; novel strategies; outcome forecast; overexpression; prevent; prognostic indicator; prostaglandin EP4 receptor; prostanoid receptor EP1; public health relevance; racial difference; receptor; receptor binding; receptor expression; receptor function; success; tumor; tumor growth; tumor progression

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.

描述(由申请人提供)： 摘要每年有20多万美国女性新诊断为乳腺癌。乳腺癌的死亡一般是由于发生转移所致。环氧合酶-2酶(COX-2)在乳腺癌中高表达，并与转移成功有关。选择性COX-2抑制剂限制了乳腺肿瘤的生长和转移，然而，最近发现与整体抑制COX-2相关的心脏毒性促使我们采取一种新的方法来靶向COX-2途径。COX-2在肿瘤中的主要产物是前列腺素E2(PGE2)，它通过与四种EP受体(EP1-4)中的每一种结合来介导生物学效应。我们已经证明，其中两个受体EP1和EP4在调节乳腺肿瘤转移方面扮演着相反的角色。EP4的药理拮抗或遗传沉默降低了转移潜能；EP1的拮抗作用增加了扩散。我们假设EP1作为一种转移抑制因子，在可能发展为播散性疾病的妇女中表达降低。此外，EP1通过依赖于自然杀伤细胞的机制控制转移。我们将通过以下具体目标来验证这些假说：利用已知长期生存的早期乳腺癌样本的独特收集，我们将(1)确定EP1的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EP1的功能意义，并确定自然杀伤细胞对EP1功能的贡献。EP1和其他G蛋白偶联受体可能在胞核和质膜中介导细胞效应。我们将(3)确定EP1的细胞位置和功能。由于所有的EP受体都与相同的配体结合，改变一个受体的功能可能会对其他EP受体功能产生不利影响。我们将(4)确定恢复保护性受体(EP1)和促转移受体(EP4)平衡的策略。对退伍军人医疗保健的潜在影响：乳腺癌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相当数量的退伍军人。目前退伍军人人口约为2600万人，其中近20万名女性退伍军人将被诊断出患有乳腺癌。因此，转移性乳腺癌死亡率的降低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EP1的表达和功能以实现这一目标奠定理论基础。 公共卫生相关性： 拟议工作与退伍军人管理局病人护理任务的相关性。每年有近20万美国人新诊断出乳腺癌。乳腺癌对社会和医疗保健有巨大的影响，由于人口老龄化，乳腺癌将变得越来越常见。鉴于退伍军人的平均年龄为58岁，乳腺癌将在未来几年影响相当数量的退伍军人。美国和波多黎各目前的退伍军人人数约为2600万人，其中近20万名女性退伍军人将在一生中被诊断出患有乳腺癌。减少这种疾病的死亡率是一个重要的目标。乳腺癌的死亡一般是由于发生局部和远处的扩散或转移。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(COX-2)酶在乳腺癌、结肠癌、前列腺癌和其他恶性肿瘤中高表达，与预后不良有关。最近对COX-2抑制剂心脏毒性的担忧促使我们研究其他治疗靶向COX-2途径的方法。我们推断，通过COX-2产物PGE2阻止下游信号传递也是有益的；然而，这一假设只得到了部分证实。我们发现，乳腺肿瘤表达所有四种已知的前列腺素E受体(EP1-4)，拮抗EP4是有益的，而EP1的拮抗实际上促进了转移。因此，EP1受体似乎具有肿瘤转移抑制的功能。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。