Prevention of Breast Cancer Development by Epidermal Fatty Acid Binding Protein (

描述（由申请人提供）：乳腺癌发病率的增加对美国和全球妇女的健康构成了重大威胁。如何预防乳腺癌的发生和寻找新的保护因子来控制乳腺癌的发生是该领域的一个巨大挑战。本提案的目的是阐明表皮脂肪酸结合蛋白（E-FABP）在预防乳腺癌发展中的保护作用，并确定E-FABP调节肿瘤相关巨噬细胞特定亚群中IFNb产生和信号传导的抗肿瘤反应的分子机制。E-FABP在巨噬细胞中大量表达，被认为是调节细胞代谢和炎症反应的重要因子。我们的初步研究表明，E-FABP缺陷型小鼠表现出显着增加乳腺肿瘤的生长和肺转移相比，野生型小鼠，表明宿主表达的E-FABP在乳腺肿瘤预防的保护作用。E-FABP表达谱的进一步分析表明E-FABP在F4/80+ CD 11b +MHCII+ CD 11 c+细胞亚群中特异性表达。微阵列和qPCR实验表明，肿瘤诱导的IFN？产生和巨噬细胞中的信号转导显着受损的E-FABP缺陷。有趣的是，IFNb刺激在M1极化过程中特异性诱导E-FABP上调。此外，o-3脂肪酸可显著增强巨噬细胞中E-FABP的表达。因此，我们推测E-FABP可能通过增强细胞脂质代谢，促进IFNb的产生、信号传导和M1样表型转换来调节巨噬细胞功能。E-FABP作为一种新的肿瘤保护因子，可通过促进巨噬细胞的抗肿瘤反应来预防乳腺癌的发生。因此，调节E-FABP活性将代表乳腺癌预防的新策略。具体目标1将确定E-FABP如何调节巨噬细胞中IFNb的产生。我们假设E-FABP是一种未鉴定的宿主衍生因子，通过影响特定巨噬细胞亚群中脂质介导的信号来调节肿瘤诱导的IFNb产生。具体目标2将确定E-FABP如何调节IFNb信号传导以促进抗肿瘤应答。我们将检验E-FABP调节的IFNb信号传导促进肿瘤特异性T淋巴细胞浸润和IFNb产生的假设，这进一步上调E-FABP表达以促进巨噬细胞M1极化用于抗肿瘤免疫。具体目标3将解决宿主来源的E-FABP是否在临床相关动物模型和人类中保护乳腺癌的发展。我们将验证E-FABP作为一种宿主源性保护因子在乳腺癌预防中的作用，并建立一种通过饮食上调E-FABP来控制乳腺癌的有效策略。总之，该项目的成功完成将揭示E-FABP作为控制乳腺癌发展的新保护因子，并帮助我们开发通过靶向E-FABP预防乳腺癌的有效策略。

DESCRIPTION (provided by applicant): The increasing incidence of breast cancer poses a major threat to women's health in the USA and worldwide. How to prevent breast tumorigenesis and to identify new protective factors for the control of breast cancer represents a great challenge in this field. The objectives of this proposal are to unravel a protective role of epidermal fatty acid binding protein (E-FABP) in preventing breast cancer development and to determine the molecular mechanisms by which E-FABP regulates IFNb production and signaling in a specific subset of tumor associated macrophages for antitumor responses. E-FABP, abundantly expressed in macrophages, has been recognized as an important regulator to coordinate cell metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP deficient mice exhibit significant increases in mammary tumor growth and lung metastasis compared to wild type mice, suggesting a protective role of host expression of E-FABP in mammary tumor prevention. Further analysis of E-FABP expression profile indicates that E-FABP is specifically expressed in the subset of F4/80+CD11b+MHCII+CD11c+ cells. Microarray and qPCR experiments show that tumor-induced IFN¿ production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly, IFNb stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover, o-3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus, we hypothesize that E-FABP may regulate macrophage function by promoting IFNb production, signaling and M1-like phenotype switch through enhancing cell lipid metabolism. E-FABP, as a new cancer protective factor, can prevent breast carcinogenesis through promoting macrophage anti-tumor responses. Therefore, modulating E-FABP activity will represent a novel strategy for breast cancer prevention. Specific Aim 1 will determine how E-FABP regulates IFNb production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFNb production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFNb signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFNb signaling promotes tumor specific T lymphocyte infiltration and IFNb production, which further upregulates E-FABP expression to facilitate macrophage M1 polarization for antitumor immunity. Specific Aim 3 will address whether host-derived E-FABP protects against breast cancer development in clinically relevant animal models and in humans. We will verify E-FABP as a host-derived protective factor in breast cancer prevention and establish an effective strategy for the control o breast cancer via dietary upregulation of E-FABP. In conclusion, successful completion of this project will reveal E-FABP as a new protective factor in control of breast cancer development and help us develop an effective strategy to prevent breast cancer via targeting E- FABP.