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

描述（由申请人提供）：NSAID的使用与乳腺癌复发率降低相关。使用临床前模型，我们已经表明，非甾体抗炎药，这是选择性和非选择性抑制剂的考克斯-2，可以减少产后乳腺肿瘤相关的淋巴管生成，侵袭和转移。鉴于淋巴结转移、肿瘤细胞侵入瘤周淋巴管和瘤周区域淋巴管密度（LVD）增加与许多人类癌症（包括乳腺癌）转移增加相关，新淋巴管形成可能在肿瘤细胞播散中起关键作用。然而，对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。我们已经确定了乳腺发育的发育窗口，促进乳腺肿瘤转移，其特征在于考克斯-2依赖性淋巴管生成。提出的目标将确定潜在的考克斯-2依赖的乳腺淋巴管生成的机制，这可能会促进增加转移的年轻妇女的乳腺癌。具体目标1：将确定乳腺肿瘤细胞淋巴源性扩散的临床前模型中考克斯-2、VEGF-C和Sem 7 a之间的关系。具体目标二：将通过研究我们的年轻女性队列和患者来源的异种移植物中淋巴管标志物考克斯-2、VEGF-C和Sem 7a的蛋白质和mRNA表达，分析考克斯-2/VEGF-C/Sem 7a信号传导对年轻女性乳腺癌的贡献。这些目标所揭示的机制将扩大我们对考克斯-2抑制剂（NSAID）如何提高年轻乳腺癌患者生存率的理解。

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.