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

• 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
• 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

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.

项目总结/摘要 尽管治疗取得了重大进展，但仍有妇女死于乳腺癌，特别是三阴性乳腺癌。 乳腺癌（TNBC）。超过50%的TNBC女性循环甘油三酯（TG）升高， 这些升高的水平与乳腺癌存活率降低有关。虽然两者之间的联系 高甘油三酯血症（HTG）和TNBC在流行病学研究中有很好的描述，检查和治疗TG水平 在患有TNBC的女性中，这不是标准临床护理的一部分。为了了解HTG与人类基因组之间的 和TNBC进展，我们采用与其他代谢性疾病分离的高甘油三酯血症的临床前模型， 异常在我们的初步研究中，我们发现HTG小鼠生长更快， 在TNBC的鼠模型中的转移。HTG小鼠表现出极低密度升高的脂质谱 脂蛋白（VLDL）和与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，我们发现一些与胆固醇合成相关的基因， 过氧化物酶体增殖物激活受体（PPAR）信号转导在TNBC中下调， 模型，而细胞骨架相关基因上调。由于这些基因表达变化以前 与缺氧相关的特征，我们检查了脂质过氧化产物， HTG小鼠肿瘤中的过氧化固醇。此外，我们发现p42/44磷酸化水平增加， 丝裂原活化蛋白激酶（MAPK）和上皮间质转化（EMT）标志物。VLDL结合 VLDL受体（VLDLR）是乳腺癌基因特征的一部分，与缺氧相关， 在TNBC的基底样亚型上高度表达。VLDLR在乳腺癌中的高表达已被证实是乳腺癌的一个重要特征。 与癌症转移相关，并且其在基底样TNBC中的表达与癌症转移的50%降低相关。 无复发生存率。因此，我们假设HTG通过以下方式促进TNBC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，从而在以下情况下提高了肿瘤存活率： 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驱动的肿瘤细胞中的重要性。 使用患者来源的异种移植物的TNBC生长和转移。其次，我们将研究一个 TNBC中脂质过氧化产物丰富。最后，我们将探索降低TG的治疗策略， 成功的研究可以很容易地转化为临床护理，以改善HTG和TNBC女性的结局。