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

脂肪细胞/巨噬细胞脂肪酸结合蛋白在乳腺癌发生中的作用

• 批准号: 8755020
• 负责人: Bing Li
• 金额: $ 32.29万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-23 至 2015-01-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755020
• 关键词: Address; Adipocytes; Animal Model; Basic Science; Behavior; Biopsy; Blood Circulation; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Cell Cycle Regulation; Cells; Clinical; Cytosol; Data; Development; Environment; Human; Infiltration; Inflammatory; Link; Mammary Neoplasms; Mediating; Metabolic; Mitotic Cell Cycle; Modification; Molecular; Mus; Neoplasm Metastasis; Obesity; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Population; Protein Deficiency; Role; Signal Transduction; Survival Rate; Testing; Therapeutic; Tissues; Up-Regulation; Woman; Women' s Health; anticancer research; base; breast tumorigenesis; cancer risk; cancer therapy; design; fatty acid-binding proteins; in vivo; inhibitor/antagonist; killings; macrophage; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel strategies; outcome forecast; protein expression; public health relevance; research study; response; tumor; tumor growth; tumor progression; tumorigenesis

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.

描述（由申请人提供）：尽管最近生存率有所提高，但乳腺癌每年仍导致全球近50万妇女死亡。巨噬细胞和脂肪细胞作为乳腺癌间质中两个最主要的细胞群，在乳腺肿瘤的发生和发展中起着核心作用。因此，这些细胞中的修饰可以极大地影响肿瘤行为。本提案的目的是确定脂肪细胞/巨噬细胞脂肪酸结合蛋白（A-FABP）在促进乳腺癌发展中的作用，通过同时靶向巨噬细胞和脂肪细胞，并开发抑制剂来调节A-FABP活性用于乳腺癌治疗。A-FABP在巨噬细胞和脂肪细胞中大量表达，已被鉴定为这些细胞中代谢和炎症途径的中心调节剂。我们的初步研究表明，A-FABP在人类和小鼠乳腺癌/乳腺癌中显著上调。响应于肿瘤刺激，细胞质A-FABP表达在肿瘤相关巨噬细胞（TAM）中显著升高，而循环A-FABP主要由脂肪细胞释放。更重要的是，A-FABP缺陷改变巨噬细胞表型，并保护小鼠免受乳腺肿瘤生长和转移。虽然肥胖与乳腺癌患者的预后不良和死亡率增加有关，但这种联系的机制仍不清楚。我们发现肥胖增加了细胞质和循环中的A-FABP，并促进乳腺癌的进展。A-FABP可能通过调节巨噬细胞和脂肪细胞功能将肥胖和乳腺癌联系起来。因此，我们假设，A-FABP，作为一个未确定的联系基础肥胖-乳腺癌的关联，促进乳腺癌的发展，通过增强巨噬细胞和脂肪细胞的促肿瘤功能。因此，调节A-FABP活性将代表乳腺癌治疗的新策略。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促肿瘤环境。具体目标2将描述脂肪细胞释放的循环A-FABP如何促进乳腺癌侵袭。实验将被设计来检验由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以增加其侵袭性而促进乳腺癌进展的假设。具体目标3将解决肥胖是否通过增加A-FABP表达促进乳腺癌。我们认为，A-FABP代表了一个未确定的因素，肥胖，以促进乳腺癌的风险和抑制剂抑制A-FABP可能会抑制乳腺癌的发展和进展。总之，所收集的数据将帮助我们揭示A-FABP在乳腺癌发展中的关键作用，并确定潜在的乳腺癌治疗的特定A-FABP抑制剂。