Understanding how elevated triglycerides contribute to triple negative breast cancer growth and metastasis

了解甘油三酯升高如何导致三阴性乳腺癌生长和转移

基本信息

批准号：
10522185
负责人：
Emily Jane Gallagher
金额：
$ 52.32万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522185
关键词：
Adult Affect Alcohols Apolipoproteins Biological Blood Circulation Breast Cancer gene Carbohydrates Cardiovascular system Caring Cells Cholesterol Clinical Trials Cytoskeleton Development Diabetes Mellitus Diet Disease Energy-Generating Resources Epidemiology Epidermal Growth Factor Receptor Estrogen Receptors Fatty Acids Gene Expression Genes Genetically Engineered Mouse Glycerol Goals Growth Human Hydroxycholesterols Hypertriglyceridemia Hypoxia Immunocompetent Link Lipid Peroxidation Lipids Lipoprotein Binding Measures Metabolic Metabolism Metastatic Neoplasm to the Lung Mitogen-Activated Protein Kinases Modeling Mus Neoplasm Metastasis Newly Diagnosed Obesity Oncology Peroxisome Proliferator-Activated Receptors Phospholipids Phosphorylation Pre-Clinical Model Primary Neoplasm Prognosis Receptor Signaling Recurrence Research Serum Signal Transduction Signaling Molecule Sterols Therapeutic Thyroid Diseases Translating Triglycerides VLDL receptor Very low density lipoprotein Woman aggressive breast cancer breast cancer diagnosis breast cancer progression breast cancer survival cancer cell cancer subtypes clinical care clinically translatable epidemiology study epithelial to mesenchymal transition genetic signature improved outcome lipidome malignant breast neoplasm molecular subtypes mortality mouse model neutrophil novel therapeutic intervention novel therapeutics patient derived xenograft model preclinical study progesterone receptor negative rapid growth receptor expression transcriptome sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth tumor hypoxia tumor microenvironment tumor-immune system interactions uptake very low density lipoprotein triglyceride

项目摘要

Project Summary / Abstract Despite significant advances in treatment, women are still dying from breast cancer, particularly triple negative breast cancer (TNBC). More than 50% of women with TNBC have elevated circulating triglycerides (TGs), and these elevated levels are associated with reduced breast cancer survival. While the link between hypertriglyceridemia (HTG) and TNBC is well described in epidemiology studies, checking and treating TG levels in women with TNBCs are not part of standard clinical care. To understand the biological links between HTG and TNBC progression, we employ pre-clinical models of hypertriglyceridemia in isolation from other metabolic abnormalities. In our preliminary studies, we have found that the mice with HTG develop more rapid growth and metastasis in murine models of TNBC. The HTG mice demonstrated lipid profiles with elevated very low density lipoprotein (VLDL), and high circulating of phospholipids associated with elevated VLDL. Examining RNA sequencing gene expression, we found that a number of genes associated with cholesterol synthesis and peroxisome proliferator activated receptor (PPAR) signaling were downregulated in the TNBC from our HTG models, while cytoskeleton related genes were upregulated. As these gene expression changes have previously been related to hypoxia signatures, we examined lipid peroxidation products and found higher levels of lipid peroxidation sterols in the tumors from the HTG mice. In addition, we found increased phosphorylation of p42/44 mitogen activated protein kinase (MAPK) and epithelial to mesenchymal transition (EMT) markers. VLDL binds to the VLDL receptor (VLDLR), which is part of a breast cancer gene signature that is associated hypoxia and is highly expressed on the basal-like subtype of TNBC. High VLDLR expression in breast cancer has been associated with cancer metastasis, and its expression in basal-like TNBC is associated with a 50% decrease in recurrence free survival. Therefore, we hypothesized that HTG promotes TNBC growth and progression by increased VLDL uptake through the VLDLR, which contributes to lipid peroxidation in hypoxic tumors. We hypothesize that lipid peroxidation increases cell signaling which enhances tumor survival in the setting of hypoxia, and also contributes to EMT, cytoskeletal changes and changes in the tumor immune microenvironment. In this project we will explore the importance of tumor VLDLR expression in HTG-driven TNBC growth and metastasis using patient derived xenografts. Secondly, we will examine the importance of an abundant lipid peroxidation product in TNBC. Finally, we will explore therapeutic strategies to lower TG, which if successful could readily be translated into clinical care to improve outcomes for women with HTG and TNBC.

项目概要/摘要尽管治疗取得了重大进展，但女性仍然死于乳腺癌，尤其是三阴性乳腺癌乳腺癌（TNBC）。超过 50% 的 TNBC 女性循环甘油三酯 (TG) 升高，并且这些升高的水平与乳腺癌存活率降低有关。虽然之间的联系高甘油三酯血症 (HTG) 和 TNBC 在流行病学研究、检查和治疗 TG 水平中得到了充分描述患有 TNBC 的女性不属于标准临床护理的一部分。了解 HTG 之间的生物学联系和 TNBC 进展，我们采用高甘油三酯血症的临床前模型，与其他代谢性疾病分开异常。在我们的初步研究中，我们发现患有 HTG 的小鼠生长速度更快，并且 TNBC 小鼠模型中的转移。 HTG 小鼠表现出具有升高的极低密度的脂质谱脂蛋白（VLDL），以及与 VLDL 升高相关的高循环磷脂。检查RNA 通过对基因表达进行测序，我们发现许多与胆固醇合成和相关的基因过氧化物酶体增殖物激活受体 (PPAR) 信号在 TNBC 中从我们的 HTG 下调模型中，细胞骨架相关基因上调。由于这些基因表达变化之前已由于与缺氧特征有关，我们检查了脂质过氧化产物，发现脂质水平较高 HTG 小鼠肿瘤中的过氧化甾醇。此外，我们发现 p42/44 的磷酸化增加丝裂原激活蛋白激酶 (MAPK) 和上皮间质转化 (EMT) 标记物。极低密度脂蛋白结合 VLDL 受体 (VLDLR) 是乳腺癌基因特征的一部分，与缺氧相关，并且在 TNBC 的基底样亚型上高表达。乳腺癌中 VLDLR 高表达与癌症转移相关，其在基底样 TNBC 中的表达与癌症转移减少 50% 相关。无复发生存期。因此，我们假设 HTG 通过以下方式促进 TNBC 的生长和进展：通过 VLDLR 增加 VLDL 摄取，这有助于缺氧肿瘤中的脂质过氧化。我们假设脂质过氧化增加了细胞信号传导，从而增强了肿瘤在以下情况下的存活：缺氧，也有助于 EMT、细胞骨架的变化和肿瘤免疫的变化微环境。在这个项目中，我们将探讨肿瘤 VLDLR 表达在 HTG 驱动中的重要性。使用患者来源的异种移植物进行 TNBC 生长和转移。其次，我们将考察 TNBC 中含有丰富的脂质过氧化产物。最后，我们将探索降低 TG 的治疗策略，如果成功可以很容易地转化为临床护理，以改善患有 HTG 和 TNBC 的女性的预后。