Role of COX-2 in breast cancer metastasis to bone

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。环氧合酶-2（考克斯-2）过表达通过刺激上皮细胞增殖、抑制凋亡、刺激血管生成和增强细胞侵袭力在肿瘤发生中起关键作用。使用结肠癌小鼠模型的研究和临床试验的结果表明，考克斯-2是预防和治疗结肠癌的有用靶点。在不同器官部位的其他上皮癌（包括乳腺癌、前列腺癌、膀胱癌、肺癌和胰腺癌）中的研究表明，考克斯-2在这些癌症的发病机制中起重要作用。关于考克斯-2在人类乳腺癌中的具体作用知之甚少，在肿瘤转移到骨的情况下更是如此。我们的计划是检验乳腺癌细胞中增加的考克斯-2的产生是引发一系列促进乳腺癌扩散到骨骼的事件的原因这一假设。我们推测乳腺癌细胞通过考克斯-2介导的前列腺素E2（PGE 2）的产生导致尿激酶型纤溶酶原激活物（uPA）的激活，引起周围组织的破坏并允许肿瘤细胞的侵袭。在上皮癌中有证据表明，PGE 2诱导肿瘤细胞和周围组织中的uPA表达。临床研究已经证明，高水平的uPA预测乳腺癌的预后更差。已知PGE 2会激活骨重塑细胞（称为破骨细胞），从而诱导骨分解，这是骨转移的第一步。当骨被破骨细胞破坏时，生长因子被释放到周围组织中，帮助肿瘤细胞在新的部位生长和扩散。 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考克斯-2、PGE 2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，并证明考克斯-2抑制剂可以阻断这些过程，2）证明考克斯-2的过表达是在裸鼠模型中建立骨转移的关键步骤，并且考克斯-2抑制剂可以阻断向骨的转移，和3）证明与不转移到骨的乳腺癌相比，转移到骨的原发性人乳腺癌产生增加的考克斯-2水平。本研究中的实验表明，考克斯-2酶的特异性抑制剂可预防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的第一步。

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.