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

这项建议的目的是确定高脂饮食(HFD)引起的脂质失调如何与肥胖联系在一起 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BC的死亡率，但肥胖/乳腺癌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，又称脂肪脂肪酸结合蛋白) FABP4通过调节肿瘤细胞内促肿瘤活性促进肥胖相关BC 相关巨噬细胞(TAMs)和细胞外增强BC细胞的侵袭表型。因此，A- FABP可能是一个将脂代谢紊乱与肥胖/BC风险联系起来的新因素。此外，我们 观察到，摄入不同类型的HFDs可导致肥胖，包括饱和脂肪(例如 可可油)或不饱和脂肪(如橄榄油、鱼油)。然而，只有可可脂高脂饮食引起的肥胖 与A-FABP表达增加和乳腺肿瘤生长有关。这些观察结果表明 并不是所有由高脂饮食引起的肥胖都是致癌的。考虑到肥胖背后的未知联系-- 诱发BC风险，我们假设富含饱和脂肪的高密度脂蛋白通过A-FABP介导促进BC风险 免疫和新陈代谢调节。因此，A-FABP提供了一种新的治疗靶点和生物标志物 与肥胖相关的BC风险。三个相辅相成但独立的具体目标旨在解决我们的 中心假说。目的1是确定不同的HFD上调A-受体的分子机制。 不列颠哥伦比亚风险的FABP。我们将确定哪些高密度脂蛋白会增加乳腺癌的风险，并进一步剖析“坏” 脂肪促进TAM细胞内A-FABP的表达和促进细胞外A-FABP的分泌 脂肪细胞。目的2描述HFD上调的A-FABP在BC中的下游代谢机制 风险和免疫疗法。我们将描述TAMS细胞内A-FABP是如何调节FA氧化的 (FAO)/HIF2α/PD-L1免疫抑制功能途径，随后描述了细胞外A- FABP对BC细胞中的脂类代谢进行重新编程，以增强其侵袭性表型。我们将进一步 用我们独特的人源化抗体阻断A-FABP活性是否能改善A-FABP诱导的 代谢失调，降低肥胖/BC风险。目标3是评估A-FABP作为肥胖的生物标志物- 在人类中相关的BC。我们将测定A-FABP在外周血单核细胞中的功能，并测定 血清中可溶性A-FABP水平和肿瘤间质中A-FABP的表达 患有或不患有不列颠哥伦比亚省的瘦削和肥胖的女性。这项提案的成功完成将决定 HFDs在促进BC风险和确定A-FABP介导的分子和代谢机制中的作用 高脂饮食诱导肥胖/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.