The role of adipocyte/macrophage fatty acid binding protein in breast cancer deve

描述(申请人提供)：尽管最近存活率有所提高，但全世界每年仍有近50万女性死于乳腺癌。巨噬细胞和脂肪细胞作为乳腺癌间质中最主要的两种细胞群，在乳腺癌的发生发展中起着核心作用。因此，这些细胞的修饰可以极大地影响肿瘤的行为。这项建议的目的是确定脂肪细胞/巨噬细胞脂肪酸结合蛋白(A-FABP)通过同时靶向巨噬细胞和脂肪细胞在促进乳腺癌发展中的作用，并开发用于乳腺癌治疗的调节A-FABP活性的抑制剂。A-FABP在巨噬细胞和脂肪细胞中大量表达，被认为是这些细胞代谢和炎症途径的中心调节因子。我们的初步研究表明，A-FABP在人和小鼠乳腺癌/乳腺癌中显著上调。肿瘤相关巨噬细胞(TAMs)胞浆A-FABP表达显著增加，而循环A-FABP主要由脂肪细胞释放。更重要的是，A-FABP缺陷改变了巨噬细胞的表型，保护小鼠免受乳腺肿瘤的生长和转移。虽然肥胖与乳腺癌患者预后不良和死亡率增加有关，但这种联系的机制基础仍不清楚。我们发现，肥胖增加了胞浆和循环中的A-FABP，并促进了乳腺癌的进展。A-FABP很可能通过调节巨噬细胞和脂肪细胞的功能将肥胖和乳腺癌联系在一起。因此，我们假设A-FABP作为肥胖-乳腺癌关联的未知联系，通过增强巨噬细胞和脂肪细胞的亲肿瘤功能而促进乳腺癌的发展。因此，调控A-FABP活性将成为乳腺癌治疗的一种新策略。具体目标1将回答细胞质A-FABP如何调节乳腺癌进展中的巨噬细胞功能。我们假设，TAMS中细胞质A-FABP的上调重新编程巨噬细胞，以促进亲肿瘤环境。具体目标2将描述脂肪细胞释放的循环A-FABP如何促进乳腺癌的侵袭。实验旨在验证这样一种假设，即脂肪细胞释放的循环A-FABP通过诱导肿瘤细胞中的致癌信号增加其侵袭性而有利于乳腺癌的进展。具体目标3将解决肥胖是否通过增加A-FABP表达而促进乳腺癌。我们认为A-FABP是促进乳腺癌风险的肥胖中的一种未知因素，用抑制剂抑制A-FABP可能会抑制乳腺癌的发生和发展。总之，收集的数据将帮助我们揭示A-FABP在乳腺癌发生中的关键作用，并为潜在的乳腺癌治疗寻找特定的A-FABP抑制剂。

DESCRIPTION (provided by applicant): Despite recent improvements in survival rates, breast cancer still kills nearly half-a-million women worldwide annually. As the two most predominant populations in breast cancer stroma, macrophages and adipocytes play central roles in breast tumorigenesis and progression. Thereby, modifications in these cells can greatly influence tumor behavior. The objectives of this proposal are to determine the role of adipocyte/macrophage fatty acid binding protein (A-FABP) in promoting breast cancer development through simultaneously targeting both macrophages and adipocytes and to develop inhibitors to modulate A-FABP activity for breast cancer therapy. A-FABP, abundantly expressed in macrophages and adipocytes, has been identified as a central regulator of metabolic and inflammatory pathways in these cells. Our preliminary studies demonstrate that A- FABP is significantly upregulated in human and murine breast/mammary cancers. In response to tumor stimulation, cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs) whereas circulating A-FABP is mainly released by adipocytes. More importantly, A-FABP deficiency alters macrophage phenotype and protects mice against mammary tumor growth and metastasis. While obesity is associated with poor prognosis and increased mortality in patients with breast cancer, the mechanistic basis for this association remains unclear. We found that obesity increases A-FABP in both cytosol and the circulation, and promotes breast cancer progression. It is likely that A-FABP links obesity and breast cancer via regulating macrophage and adipocyte functions. Thus, we hypothesize that A-FABP, as an unidentified link underlying the obesity-breast cancer association, promotes the development of breast cancer through enhancing pro-tumor functions of macrophages and adipocytes. Therefore, modulating A-FABP activity will represent a novel strategy for breast cancer therapy. Specific Aim 1 will answer how cytoplasmic A-FABP regulates macrophage functions for breast cancer progression. We hypothesize that upregulation of cytoplasmic A-FABP in TAMs reprograms the macrophages to promote a pro-tumor environment. Specific Aim 2 will delineate how circulating A-FABP released by adipocytes contributes to breast cancer invasion. Experiments will designed to test the hypothesis that circulating A-FABP released by adipocytes favors breast cancer progression by inducing oncogenic signaling in tumor cells to increase their aggressiveness. Specific Aim 3 will address whether obesity promotes breast cancer through increasing A-FABP expression. We propose that A-FABP represents an unidentified factor in obesity to promote breast cancer risk and inhibition of A-FABP with inhibitors may suppress breast cancer development and progression. In conclusion, the data collected will help us unravel the critical role of A-FABP in breast cancer development and identify specific A- FABP inhibitors for potential breast cancer therapy.