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.

项目摘要/摘要 尽管在治疗方面取得了重大进展，但仍有女性死于乳腺癌，尤其是三重阴性。 乳腺癌(TNBC)。超过50%患有TNBC的女性循环甘油三酯(TGS)升高，并且 这些升高的水平与乳腺癌存活率的降低有关。而两者之间的联系 高甘油三酯血症(HTG)和TNBC在流行病学研究、检查和治疗TG水平中有很好的描述 对于患有TNBCs的妇女，TNBCs不是标准临床护理的一部分。了解HTG和HTG之间的生物学联系 和TNBC进展，我们使用与其他代谢分离的高甘油三酯血症的临床前模型 异常现象。在我们的初步研究中，我们发现HTG组小鼠生长发育更快， 小鼠TNBC模型的转移。HTG小鼠表现出极低密度升高的血脂谱。 脂蛋白(VLDL)，以及与VLDL升高相关的磷脂循环增加。检查RNA 对基因表达进行测序后，我们发现了一些与胆固醇合成和 我们的HTG下调了TBC中PPAR信号的表达 模型组，细胞骨架相关基因表达上调。因为这些基因表达的变化以前 与低氧信号有关，我们检查了脂质过氧化产物，发现脂质水平较高 HTG小鼠肿瘤组织中的过氧化甾醇。此外，我们还发现p42/44的磷酸化增加。 丝裂原活化蛋白激酶(MAPK)和上皮间充质转化(EMT)标志物。极低密度脂蛋白结合 与极低密度脂蛋白受体(VLDLR)有关，VLDLR是乳腺癌基因标志的一部分，与缺氧有关，是 高表达于基底样亚型的TNBC。VLDLR在乳腺癌中的高表达 与肿瘤转移有关，其在基底细胞样TNBC中的表达与 无复发存活率。因此，我们假设HTG通过以下方式促进TNBC的生长和发展 通过极低密度脂蛋白受体增加对极低密度脂蛋白的摄取，这有助于缺氧性肿瘤的脂质过氧化。我们 假设脂质过氧化增加细胞信号从而提高肿瘤存活率 缺氧，也有助于EMT、细胞骨架的改变和肿瘤免疫的改变 微环境。在这个项目中，我们将探索肿瘤VLDLR表达在HTG驱动中的重要性 使用患者来源的异种移植物的TNBC生长和转移。其次，我们将研究一项 TNBC中存在丰富的脂质过氧化产物。最后，我们将探索降低甘油三酯的治疗策略，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的妇女的预后。