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: 6799941
• 负责人: ANTHONY LUCCI
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799941
• 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开发预防和治疗乳腺癌的策略。环氧合酶-2(COX-2)的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，在肿瘤的发生发展中起着关键作用。使用小鼠结肠癌模型的研究和临床试验的结果表明，COX-2是预防和治疗结肠癌的有用靶点。对乳腺癌、前列腺癌、膀胱癌、肺癌和胰腺癌等不同器官部位的其他上皮性肿瘤的研究表明，COX-2在这些癌症的发病机制中起着重要作用。人们对COX-2在人类乳腺癌中的具体作用知之甚少，对于肿瘤转移到骨的情况更是知之甚少。我们的计划是测试这一假说，即乳腺癌细胞中COX-2的产生增加是引发一系列促进乳腺癌扩散到骨骼的事件的原因。我们假设COX-2介导的前列腺素E_2(PGE_2)的产生导致尿激酶型纤溶酶原激活物(UPA)的激活，从而导致周围组织的破坏和肿瘤细胞的侵袭。有证据表明，在上皮性癌症中，PGE2可以诱导肿瘤细胞和周围组织中uPA的表达。临床研究已经证明，高水平的uPA预示着乳腺癌更糟糕的结局。已知PGE2可引起骨重建细胞(称为破骨细胞)的激活，以诱导骨破坏，这是骨转移的第一步。当破骨细胞分解骨骼时，生长因子会释放到周围的组织中，帮助肿瘤细胞在新的位置生长和扩散。 该项目的具体目标是：1)证明已知转移到骨的乳腺癌细胞系过表达COX-2、PGE2和uPA，从而允许癌细胞侵袭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的过表达是建立裸鼠模型骨转移的关键步骤，并且COX-2抑制剂可以阻止骨转移，以及3)证明与不转移到骨的乳腺癌相比，转移到骨的原发乳腺癌会产生更高水平的COX-2。我们提出的研究中的实验将表明，COX-2酶的特定抑制剂可以防止乳腺癌骨转移的形成。从我们拟议的研究中收集的数据是开发乳腺癌化学预防和治疗临床试验的重要第一步。

项目成果

Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow.

• DOI: 10.1007/s10549-008-0135-x
• 发表时间: 2009-09
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Lucci A;Krishnamurthy S;Singh B;Bedrosian I;Meric-Bernstam F;Reuben J;Broglio K;Mosalpuria K;Lodhi A;Vincent L;Cristofanilli M
• 通讯作者: Cristofanilli M

COX-2 overexpression increases motility and invasion of breast cancer cells.

• DOI: 10.3892/ijo.26.5.1393
• 发表时间: 2005-05
• 期刊: International Journal of Oncology
• 影响因子: 5.2
• 作者: Balraj Singh;Jacob A. Berry;A. Shoher;Vijayalakshmi Ramakrishnan;A. Lucci

Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application?

• DOI: 10.1586/14737140.7.10.1463
• 发表时间: 2007-10
• 期刊: Expert Review of Anticancer Therapy
• 影响因子: 3.3
• 作者: J. Lang;C. Hall;Balraj Singh;A. Lucci

Overexpression of COX-2 in celecoxib-resistant breast cancer cell lines.

• DOI: 10.1016/j.jss.2010.04.061
• 发表时间: 2010-10
• 期刊: The Journal of surgical research
• 作者: Singh B;Irving LR;Tai K;Lucci A
• 通讯作者: Lucci A

Role of COX-2 in tumorospheres derived from a breast cancer cell line.

• DOI: 10.1016/j.jss.2010.03.003
• 发表时间: 2011-06-01
• 期刊: The Journal of surgical research
• 作者: Singh B;Cook KR;Vincent L;Hall CS;Martin C;Lucci A
• 通讯作者: Lucci A