Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk

该提案的目的是确定高脂饮食 (HFD) 引起的脂质失调如何与肥胖相关 乳腺癌 (BC) 风险增加。流行病学研究证实肥胖会增加患病风险 和乳腺癌死亡率，但肥胖/乳腺癌关联的分子机制在很大程度上仍然存在 未知。我们最近的研究表明，脂质伴侣 A-FABP（脂肪脂肪酸结合蛋白，也 FABP4）通过细胞内调节肿瘤中的促肿瘤活性来促进肥胖相关的 BC 相关巨噬细胞 (TAM) 和细胞外增强 BC 细胞的侵袭性表型。因此，A- FABP 可能代表了将脂质代谢失调与肥胖/乳腺癌风险联系起来的一个新因素。此外，我们 观察到肥胖可以通过食用不同类型的 HFD 引起，包括饱和脂肪（例如脂肪）。 可可脂）或不饱和脂肪（例如橄榄油、鱼油）。然而，只有可可脂 HFD 引起的肥胖才有效。 与 A-FABP 表达增加和乳腺肿瘤生长相关。这些观察表明 并非所有 HFD 引起的肥胖都具有致瘤性这一新概念。鉴于肥胖背后的不确定联系—— 诱发 BC 风险，我们假设富含饱和脂肪的 HFD 通过 A-FABP 介导促进 BC 风险 免疫和代谢调节。因此，A-FABP 为以下疾病提供了新的治疗靶点和生物标志物： 肥胖相关的 BC 风险。三个互补但独立的具体目标旨在解决我们的问题 中心假设。目标 1 是确定不同 HFD 上调 A- 的分子机制 BC 风险的 FABP。我们将确定哪些 HFD 会增加乳腺肿瘤风险，并进一步剖析“坏”是如何产生的 脂肪驱动 TAM 中细胞内 A-FABP 表达，并促进细胞外 A-FABP 分泌 脂肪细胞。目标 2 是描绘 BC 中 HFD 上调的 A-FABP 的下游代谢机制 风险和免疫治疗。我们将描述 TAM 中的细胞内 A-FABP 如何调节 FA 氧化 (FAO)/HIF2α/PD-L1 通路发挥免疫抑制功能，随后描述细胞外 A- FABP 重新编程 BC 细胞中的脂质代谢谱，以增强其攻击性表型。我们将进一步 评估用我们独特的人源化抗体阻断 A-FABP 活性是否可以改善 A-FABP 诱导的 代谢失调并降低肥胖/BC 风险。目标 3 是评估 A-FABP 作为肥胖生物标志物 - 与人类相关的BC。我们将测定外周单核细胞中 A-FABP 的功能并测量 血清中可溶性 A-FABP 水平和肿瘤基质中 A-FABP 表达 有或没有 BC 的瘦和肥胖女性。该提案的成功完成将决定“坏 HFDs”可促进 BC 风险并确定 A-FABP 介导的分子和代谢机制 HFD 诱导的肥胖/BC 风险中的促肿瘤活性。

The objective of this proposal is to determine how high fat diet (HFD)-induced lipid dysregulation links obesity with increased breast cancer (BC) risk. Epidemiologic studies have confirmed that obesity increases the risk and mortality of BC, but the molecular mechanisms of obesity/breast cancer associations remain largely unknown. Our recent studies demonstrate that lipid chaperone A-FABP (adipose fatty acid binding protein, also known as FABP4) promotes obesity-associated BC by intracellular regulating pro-tumor activity in tumor associated macrophages (TAMs) and extracellular enhancing aggressive phenotype of BC cells. Thus, A- FABP might represent a new factor linking dysregulated lipid metabolism with obesity/BC risk. Moreover, we observed that obesity can be induced by consumption of different types of HFDs, including saturated fats (e.g. cocoa butter) or unsaturated fats (e.g. olive oil, fish oil). However, only cocoa butter HFD-induced obesity was associated with increased A-FABP expression and mammary tumor growth. These observations suggest a novel concept that not all HFD-induced obesity is tumorigenic. Given the undefined links underlying obesity- induced BC risk, we hypothesized that HFDs rich in saturated fats promote BC risk through A-FABP-mediated immune and metabolic regulations. As such, A-FABP offers a novel therapeutic target and biomarker for obesity-associated BC risk. Three complementary but independent specific aims are designed to address our central hypothesis. Aim 1 is to determine the molecular mechanisms by which different HFDs upregulate A- FABP for BC risk. We will identify which HFDs promote mammary tumor risk and further dissect how the “bad” fat drives intracellular A-FABP expression in TAMs and promotes extracellular A-FABP secretion from adipocytes. Aim 2 is to delineate the downstream metabolic mechanisms of HFD-upregulated A-FABP in BC risk and immunotherapy. We will delineate how intracellular A-FABP in TAMs regulates the FA oxidation (FAO)/HIF2α/PD-L1 pathway for immune suppressive function, followed by delineation of how extracellular A- FABP reprograms lipid metabolic profile in BC cells to enhance their aggressive phenotype. We will further evaluate if blocking A-FABP activity with our unique humanized antibodies improves A-FABP-induced metabolic dysregulation and reduces obesity/BC risk. Aim 3 is to evaluate A-FABP as a biomarker for obesity- associated BC in humans. We will determine the function of A-FABP in peripheral monocytes and measure the levels of soluble A-FABP in serum and A-FABP expression in tumor stroma using specimens collected from lean and obese women with or without BC. Successful completion of this proposal will determine the “bad HFDs” in promoting BC risk and identify the molecular and metabolic mechanisms by which A-FABP mediates the pro-tumorigenic activities in HFD-induced obesity/BC risk.