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

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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Emily Jane Gallagher其他文献

Monitoring of estradiol levels in premenopausal women receiving adjuvant abemaciclib and ovarian function suppression
  • DOI:
    10.1007/s10549-024-07439-y
  • 发表时间:
    2024-08-07
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Alaina J. Kessler;Rima Patel;Emily Jane Gallagher;Tianxiang Sheng;Damodara Rao Mendu;Amy Tiersten;Paula Klein;Aarti S. Bhardwaj;Anupama Goel;Joseph A. Sparano;Theresa Shao;Julie Fasano
  • 通讯作者:
    Julie Fasano

Emily Jane Gallagher的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Emily Jane Gallagher', 18)}}的其他基金

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:
    10670404
  • 财政年份:
    2022
  • 资助金额:
    $ 52.32万
  • 项目类别:
Cholesterol promotes breast cancer progression: establishing the mechanisms
胆固醇促进乳腺癌进展:建立机制
  • 批准号:
    9321867
  • 财政年份:
    2014
  • 资助金额:
    $ 52.32万
  • 项目类别:
Cholesterol promotes breast cancer progression: establishing the mechanisms
胆固醇促进乳腺癌进展:建立机制
  • 批准号:
    8804581
  • 财政年份:
    2014
  • 资助金额:
    $ 52.32万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 52.32万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了