Role of COX-2 in breast cancer metastasis to bone

COX-2在乳腺癌骨转移中的作用

• 批准号: 6687138
• 负责人: ANTHONY LUCCI
• 金额: $ 15.05万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687138
• 关键词: antiinflammatory agents; bone neoplasms; breast neoplasms; clinical research; enzyme activity; enzyme biosynthesis; enzyme inhibitors; extracellular matrix; growth factor; human subject; immunoprecipitation; metastasis; osteoclasts; pathologic bone resorption; patient oriented research; plasminogen activator; prostaglandin E; prostaglandin endoperoxide synthase; transfection; western blottings

DESCRIPTION (provided by applicant): Our major long-term goal is to develop strategies for the prevention and treatment of breast cancer through translational research. Cyclooxygenase-2 (COX-2) overexpression plays a key role in tumorigenesis by stimulating epithelial cell proliferation, inhibiting apoptosis, stimulating angiogenesis, and enhancing cell invasiveness. Studies using mouse models of colon cancer, and the results of clinical trials have shown COX-2 to be a useful target for the prevention and treatment of colon cancer. Studies in other epithelial cancers at different organ sites, including breast, prostate, bladder, lung, and pancreas, suggest that COX-2 plays an important role in the pathogenesis of these cancers. Little is known about the specific role of COX-2 in human breast cancer, and even less so in case of tumor metastasis to the bone. Our plan is to test the hypothesis that increased production of COX-2 in the breast cancer cells is responsible for initiating a series of events that facilitate the spread of breast cancer to the bone. We hypothesize that COX-2- mediated production of prostaglandin E2 (PGE2) by breast cancer cells results in activation of urokinase-type plasminogen activator (uPA), causing the destruction of surrounding tissues and allowing invasion of tumor cells. There is evidence in epithelial cancers that PGE2 induces uPA expression in both tumor cells and surrounding tissues. Clinical studies have documented that high levels of uPA predict a worse outcome from breast cancer. PGE2 is known to cause the activation of bone remodeling cells, called osteoclasts, to induce bone breakdown, the first step in metastasis to bone. When bone is broken down by osteoclasts, growth factors are released into the surrounding tissue, helping tumor cells to grow and spread at their new site. Specific Aims of this project are: 1) to demonstrate that breast cancer cell lines known to metastasize to bone overexpress COX-2, PGE2, and uPA thus allowing the cancer cells to invade the extracellular matrix and to stimulate osteoclast-mediated bone resorption, and to demonstrate that COX-2 inhibitors can block these processes, 2) to demonstrate that overexpression of COX-2 is a key step in establishing bone metastases in a nude mouse model and that a COX-2 inhibitor can block metastasis to the bone, and 3) to demonstrate that primary human breast cancers that metastasize to the bone produce increased levels of COX-2 as compared to breast cancers that do not metastasize to the bone. The experiments in our proposed study will show that specific inhibitors of COX-2 enzyme prevent formation of bone metastases from breast cancer. The data gathered from our proposed study is the important first step in developing clinical trials for the chemoprevention and treatment of breast cancer.

描述（由申请人提供）： 我们的主要长期目标是通过转化研究制定预防和治疗乳腺癌的策略。环加氧酶-2 (COX-2) 过表达通过刺激上皮细胞增殖、抑制细胞凋亡、刺激血管生成和增强细胞侵袭性，在肿瘤发生中发挥关键作用。使用结肠癌小鼠模型的研究和临床试验结果表明COX-2是预防和治疗结肠癌的有用靶点。对不同器官部位（包括乳腺癌、前列腺、膀胱、肺癌和胰腺）的其他上皮癌的研究表明，COX-2 在这些癌症的发病机制中发挥着重要作用。人们对 COX-2 在人类乳腺癌中的具体作用知之甚少，对于肿瘤骨转移的情况更是知之甚少。我们的计划是检验这样一个假设：乳腺癌细胞中 COX-2 的产生增加会引发一系列促进乳腺癌扩散到骨骼的事件。我们假设乳腺癌细胞 COX-2 介导的前列腺素 E2 (PGE2) 产生导致尿激酶型纤溶酶原激活剂 (uPA) 激活，导致周围组织破坏并允许肿瘤细胞侵袭。有证据表明，上皮癌中 PGE2 会诱导肿瘤细胞和周围组织中 uPA 的表达。临床研究证明，高水平的 uPA 预示着乳腺癌的预后会更差。众所周知，PGE2 会激活骨重塑细胞（破骨细胞），从而诱导骨分解，这是骨转移的第一步。当骨质被破骨细胞分解时，生长因子被释放到周围组织中，帮助肿瘤细胞在新部位生长和扩散。 该项目的具体目标是：1) 证明已知骨转移的乳腺癌细胞系过度表达 COX-2、PGE2 和 uPA，从而允许癌细胞侵入细胞外基质并刺激破骨细胞介导的骨吸收，并证明 COX-2 抑制剂可以阻断这些过程，2) 证明 COX-2 的过度表达是骨转移建立的关键步骤。 裸鼠模型和 COX-2 抑制剂可以阻止骨转移，3) 证明转移到骨的原发性人类乳腺癌与未转移到骨的乳腺癌相比，产生更高水平的 COX-2。我们提出的研究中的实验将表明 COX-2 酶的特异性抑制剂可防止乳腺癌骨转移的形成。从我们提出的研究中收集的数据是开展乳腺癌化学预防和治疗临床试验的重要的第一步。