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
基本信息
- 批准号:9039350
- 负责人:
- 金额:$ 33.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-09 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesBasic ScienceBehaviorBlood CirculationBreastBreast Cancer CellBreast Cancer ModelBreast Cancer TreatmentBreast Cancer therapyCell Cycle RegulationCellsClinicalCytosolDataDevelopmentEnvironmentHealthHumanInfiltrationInflammatoryLinkMammary NeoplasmsMediatingMetabolicMitotic Cell CycleModificationMusNeoplasm MetastasisObesityPathway interactionsPatientsPhenotypePlayPopulationPreventionProtein DeficiencyRoleSurvival RateTestingTherapeuticUp-RegulationWomanWomen&aposs Healthbasebreast tumorigenesiscancer riskdesignfatty acid-binding proteinsin vivoinhibitor/antagonistkillingsmacrophagemalignant breast neoplasmmortalitymouse modelneoplastic cellnovel strategiesoutcome forecastprotein expressionresearch studyresponsetumortumor growthtumor progressiontumorigenesis
项目摘要
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 increasing tumor cell 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,但乳腺癌每年仍然夺去全世界近 50 万女性的生命。作为乳腺癌基质中最主要的两个群体,巨噬细胞和脂肪细胞在乳腺肿瘤的发生和进展中发挥着核心作用。因此,这些细胞的修饰可以极大地影响肿瘤行为。该提案的目的是通过同时靶向巨噬细胞和脂肪细胞来确定脂肪细胞/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,并开发调节 A-FABP 活性的抑制剂用于乳腺癌治疗。 A-FABP 在巨噬细胞和脂肪细胞中大量表达,已被确定为这些细胞中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 在人类和小鼠乳腺癌中显着上调。响应肿瘤刺激,肿瘤相关巨噬细胞 (TAM) 中细胞质 A-FABP 表达显着升高,而循环 A-FABP 主要由脂肪细胞释放。更重要的是,A-FABP 缺乏会改变巨噬细胞表型,并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,但这种关联的机制基础仍不清楚。我们发现肥胖会增加细胞质和循环中的 A-FABP,并促进乳腺癌进展。 A-FABP 很可能通过调节巨噬细胞和脂肪细胞功能将肥胖与乳腺癌联系起来。因此,我们假设 A-FABP 作为肥胖与乳腺癌关联的一个未识别的联系,通过增强巨噬细胞和脂肪细胞的促肿瘤功能来促进乳腺癌的发展。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 如何调节巨噬细胞功能以促进乳腺癌进展。我们假设 TAM 中细胞质 A-FABP 的上调会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。实验旨在检验脂肪细胞释放的循环 A-FABP 通过增加肿瘤细胞侵袭性来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 表达而促进乳腺癌。我们认为 A-FABP 是肥胖中一种未识别的因素,会增加患乳腺癌的风险,并且用抑制剂抑制 A-FABP 可能会抑制乳腺癌的发生和进展。总之,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,并确定用于潜在乳腺癌治疗的特定 A-FABP 抑制剂。
项目成果
期刊论文数量(0)
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Bing Li其他文献
Bing Li的其他文献
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{{ truncateString('Bing Li', 18)}}的其他基金
Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk
确定 A-FABP 与脂质代谢失调引起的肥胖/乳腺癌风险相关的分子和代谢机制
- 批准号:
10683379 - 财政年份:2022
- 资助金额:
$ 33.06万 - 项目类别:
Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk
确定 A-FABP 与脂质代谢失调引起的肥胖/乳腺癌风险相关的分子和代谢机制
- 批准号:
10501614 - 财政年份:2022
- 资助金额:
$ 33.06万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10320058 - 财政年份:2021
- 资助金额:
$ 33.06万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10544533 - 财政年份:2021
- 资助金额:
$ 33.06万 - 项目类别:
E-FABP mediates n-3 fatty acid-induced tumor prevention through epigenetic control of immune cell differentiation and function
E-FABP 通过免疫细胞分化和功能的表观遗传控制介导 n-3 脂肪酸诱导的肿瘤预防
- 批准号:
10459794 - 财政年份:2021
- 资助金额:
$ 33.06万 - 项目类别:
Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
E-FABP在银屑病发病机制中的免疫调节机制
- 批准号:
10459902 - 财政年份:2021
- 资助金额:
$ 33.06万 - 项目类别:
Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis
E-FABP在银屑病发病机制中的免疫调节机制
- 批准号:
10478125 - 财政年份:2021
- 资助金额:
$ 33.06万 - 项目类别:
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