(PQA1)Toward understanding mechanisms of COX-2 driven metastasis of breast cancer

描述(由申请人提供)：非甾体抗炎药的使用与乳腺癌复发的减少有关。使用临床前模型，我们已经证明了非类固醇抗炎药是选择性和非选择性的COX-2抑制剂，可以减少产后乳腺癌相关淋巴管的生成、侵袭和转移。考虑到在包括乳腺癌在内的许多人类癌症中，淋巴结转移、肿瘤细胞对瘤周淋巴管的侵袭以及瘤周区域淋巴管密度(LVD)的增加与转移的增加有关，新淋巴管的形成可能在肿瘤细胞扩散中起关键作用。然而，肿瘤诱导的淋巴管生成可能驱动肿瘤转移的机制却知之甚少。我们已经确定了一个促进乳腺肿瘤转移的乳腺发育窗口，其特征是COX-2依赖的淋巴管生成。建议的目标将确定乳腺中依赖COX-2的淋巴管生成的潜在机制，这可能会促进年轻女性乳腺癌转移的增加。具体目的1：将确定COX-2、VEGF-C和Sem7a在乳腺肿瘤细胞淋巴扩散的临床前模型中的关系。具体目标2：通过研究淋巴管标志物COX-2、VEGF-C和Sem7a在年轻女性队列和患者来源的异种移植物中的蛋白和mRNA表达，分析COX-2/VEGF-C/Sem7a信号在年轻女性乳腺癌中的作用。这些目的揭示的机制将扩大我们对环氧合酶-2抑制剂(NSAIDs)如何提高年轻乳腺癌女性存活率的理解。

DESCRIPTION (provided by applicant): NSAID use is associated with decreased breast cancer recurrence. Using pre-clinical models we have shown that NSAIDs, which are selective and non-selective inhibitors of COX-2, can reduce postpartum breast tumor associated lymphangiogenesis, invasion, and metastasis. Given that lymph node metastasis, invasion of tumor cells into peritumor lymphatic vessels, and increased lymphatic vessel density (LVD) in the peritumor region correlate with increased metastasis in a number of human cancers including breast, new lymphatic vessel formation likely plays a key role in tumor cell dissemination. However, very little is known about the mechanisms of tumor induced lymphangiogenesis that may drive tumor metastasis. We have identified a developmental window of mammary gland development that promotes mammary tumor metastasis and is characterized by COX-2 dependent lymphangiogenesis. The proposed aims will identify mechanisms underlying COX-2 dependent lymphangiogenesis in the mammary gland, which may promote increased metastasis of young women's breast cancers. Specific Aim 1: Will determine the relationship between COX-2, VEGF-C, and Sem7a in pre-clinical models of breast tumor cell lymphogenous spread. Specific Aim 2: Will analyze the contribution of COX-2/VEGF-C/Sem7a signaling to young women's breast cancer through investigation of protein and mRNA expression of lymphatic vessel markers, COX-2, VEGF-C, and Sem7a in our young women's cohorts and in patient derived xenografts. Mechanisms uncovered by these aims will expand our understanding of how COX-2 inhibitors, NSAIDs, may improve survival rates for young women with breast cancer.