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

描述（由申请人提供）：使用非甾体抗炎药与减少乳腺癌复发有关。通过临床前模型，我们发现非甾体抗炎药是COX-2的选择性和非选择性抑制剂，可以减少产后乳腺癌相关淋巴管生成、侵袭和转移。考虑到淋巴结转移、肿瘤细胞侵入肿瘤周围淋巴管以及肿瘤周围淋巴管密度（LVD）的增加与包括乳腺癌在内的许多人类癌症的转移增加相关，新的淋巴管形成可能在肿瘤细胞传播中起关键作用。然而，关于肿瘤诱导的淋巴管生成可能驱动肿瘤转移的机制知之甚少。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依赖性淋巴管生成。提出的目的是确定乳腺中COX-2依赖性淋巴管生成的机制，这可能促进年轻女性乳腺癌转移的增加。特异性目的1：将确定COX-2， VEGF-C和Sem7a在乳腺肿瘤细胞淋巴性扩散的临床前模型中的关系。具体目标2：将通过研究年轻女性队列和患者来源的异种移植物中淋巴管标志物、COX-2、VEGF-C和Sem7a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。这些目标揭示的机制将扩大我们对COX-2抑制剂（非甾体抗炎药）如何提高年轻乳腺癌女性生存率的理解。

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.