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世界各地妇女的健康构成了重大威胁。如何预防乳腺癌的发生，寻找新的保护因素来控制乳腺癌，是这一领域的一大挑战。该提案的目的是揭示表皮脂肪酸结合蛋白(E-FABP)在预防乳腺癌发生中的保护作用，并确定E-FABP调节特定的肿瘤相关巨噬细胞中干扰素的产生和信号以进行抗肿瘤反应的分子机制。E-FABP在巨噬细胞中大量表达，被认为是协调细胞代谢和炎症途径的重要调节因子。我们的初步研究表明，与野生型小鼠相比，E-FABP缺陷小鼠的乳腺肿瘤生长和肺转移显著增加，提示E-FABP宿主表达在预防乳腺肿瘤中具有保护作用。进一步分析E-FABP的表达谱表明，E-FABP在F4/80+CD11b+MHCII+CD11c+细胞亚群中特异表达。基因芯片和定量聚合酶链式反应实验表明，E-FABP缺乏可显著抑制肿瘤诱导的巨噬细胞产生干扰素和信号。有趣的是，干扰素γ刺激特异性地诱导E-FABP在M1极化过程中上调。此外，ω-3脂肪酸可显著增强巨噬细胞E-FABP的表达。因此，我们推测E-FABP可能通过促进细胞脂代谢促进干扰素的产生、信号转导和M1样表型转换来调节巨噬细胞的功能。E-FABP作为一种新的癌症保护因子，可通过促进巨噬细胞抗肿瘤反应来预防乳腺癌的发生。因此，调控E-FABP的活性将成为乳腺癌预防的一种新策略。具体目标1将确定E-FABP如何调节巨噬细胞中干扰素的产生。我们假设E-FABP是一种未知的宿主衍生因子，通过影响巨噬细胞特定亚群中的脂质介导信号来调节肿瘤诱导的干扰素的产生。具体目标2将确定E-FABP如何调节干扰素？？信号以促进抗肿瘤反应。我们将验证这一假设，即E-FABP调节的干扰素？信号促进肿瘤特异性T淋巴细胞的渗透和干扰素γ的产生，从而进一步上调E-FABP的表达，促进巨噬细胞M1极化，从而达到抗肿瘤免疫的目的。具体目标3将解决宿主来源的E-FABP是否在临床相关的动物模型和人类中预防乳腺癌的发展。我们将验证E-FABP在乳腺癌预防中是宿主来源的保护因子，并通过饮食上调E-FABP来建立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的保护因素，并帮助我们制定一种通过靶向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 IFNß 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 IFNß production and signaling in macrophages are significantly impaired by E-FABP deficiency. Interestingly, IFNγ stimulation specifically induces E-FABP upregulation in the process of M1 polarization. Moreover, ω-3 fatty acids can greatly enhance E-FABP expression in macrophages. Thus, we hypothesize that E-FABP may regulate macrophage function by promoting IFNß 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 IFNß production in macrophages. We hypothesize that E-FABP is an unidentified host-derived factor to regulate tumor-induced IFNß production through impacting lipid-mediated signals in specific subsets of macrophages. Specific Aim 2 will determine how E-FABP regulates IFNß signaling to promote anti-tumor responses. We will test the hypothesis that E-FABP-regulated IFNß signaling promotes tumor specific T lymphocyte infiltration and IFNγ 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.