Cyclooxygenase Modulators of Immune Function in Breast Cancer

环氧合酶-2（考克斯-2）酶通常在上皮癌中过表达，并且与上皮癌相关。 乳腺癌和其他恶性肿瘤预后差。流行病学研究表明，长期使用 考克斯抑制剂与原发性乳腺癌、结肠癌、肺癌和其他癌症的低风险相关。我们的长期 我们的目标是开发预防或治疗转移性乳腺癌的疗法。我们采用了临床前 和临床模型来定义促成肿瘤转移的因素。我们的研究表明，考克斯-2 活性导致侵袭性乳腺癌行为，考克斯-2抑制剂控制肿瘤生长， 通过免疫依赖性机制转移。初步研究支持这一假设，即考克斯 抑制剂改变肿瘤细胞的内在特性，改变刺激和抑制配体的平衡， 接合免疫效应细胞上的受体。这些调节使肿瘤靶点对肿瘤细胞的生长更敏感。 免疫细胞介导的裂解。使用药理学和遗传学方法，目标1将确定 天然杀伤配体调节的功能意义。考克斯-2产物PGE 2介导细胞凋亡， 通过四种EP受体进行信号传导。我们的研究表明了一种新的方法来抑制乳腺癌 通过靶向选择性EP受体来转移癌症。第二个目标将继续确定相关的 调节转移行为和NK活性的EP受体途径。第三个目标将确定 局部乳腺癌中肿瘤和宿主细胞表达的EP受体。使用大量的井- 特征性的人类乳腺肿瘤，其长期生存是已知的，第四个目标将确定EP是否 受体或NK配体表达与人乳腺癌的行为相关。这些研究 将检验NK激活配体的表达与更好的预后相关的假设， 一些EP受体的存在表明更差的结果。乳腺癌治疗新进展 癌症大大改善了患有依赖性疾病的妇女的前景。较少治疗 对于非依赖性疾病和晚期疾病，可提供选择。基于免疫的疗法是 现有疗法的有吸引力的替代品，拟议的研究可能会确定一种策略， 抗肿瘤免疫应答的先天性和适应性两方面。

The cyclooxygenase-2 (COX-2) enzyme is commonly overexpressed in epithelial cancers and is associated with a poor prognosis in breast and other malignancies. Epidemiological studies show that chronic use of COX inhibitors is associated with a lower risk of primary breast, colon, lung and other cancers. Our long term goal is to develop therapies that will prevent or treat metastatic breast cancer. We have employed preclinical and clinical models to define the factors that contribute to tumor metastasis. Our studies show that COX-2 activity contributes to aggressive breast cancer behavior and that COX-2 inhibitors control tumor growth and metastasis by immune-dependent mechanisms. Preliminary studies support the hypothesis that COX inhibitors alter intrinsic properties of tumor cells, altering the balance of stimulating and inhibiting ligands that engage receptors on immune effector cells. These modulations render the tumor target more sensitive to immune cell-mediated lysis. Using pharmacologic and genetic approaches, Aim 1 will determine the functional significance of Natural Killer-ligand modulations. The COX-2 product PGE2 mediates cellular responses by signaling through four EP receptors. Our studies indicate a novel approach to inhibit breast cancer metastasis by targeting selective EP receptors. The second Aim will continue to identify the relevant EP receptor pathways that modulate metastatic behavior and NK activities. The third Aim will define the role of EP receptors expressed by tumor and host cells in localized breast cancer. Using a large series of well- characterized human breast tumors, for which long term survival is known, the fourth Aim will determine if EP receptors or NK ligand expression have relevance to the behavior of human breast cancers. These studies will test the hypothesis that expression of NK-activating ligands is associated with a better prognosis but the presence of some EP receptors indicates a worse outcome. Recent advances in the treatment of breast cancer have greatly improved the outlook for women with hormone-dependent disease. Fewer treatment options are available for hormone-independent and advanced disease. Immune-based therapies are attractive alternatives to existing therapies and the proposed studies may identify a strategy that would boost both innate and adaptive arms of the antitumor immune response.