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:
- 金额:$ 52.32万
- 依托单位:
- 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:
- 关键词:AdultAffectAlcoholsApolipoproteinsBiologicalBlood CirculationBreast Cancer geneCarbohydratesCardiovascular systemCaringCellsCholesterolClinical TrialsCytoskeletonDevelopmentDiabetes MellitusDietDiseaseEnergy-Generating ResourcesEpidemiologyEpidermal Growth Factor ReceptorEstrogen ReceptorsFatty AcidsGene ExpressionGenesGenetically Engineered MouseGlycerolGoalsGrowthHumanHydroxycholesterolsHypertriglyceridemiaHypoxiaImmunocompetentLinkLipid PeroxidationLipidsLipoprotein BindingMeasuresMetabolicMetabolismMetastatic Neoplasm to the LungMitogen-Activated Protein KinasesModelingMusNeoplasm MetastasisNewly DiagnosedObesityOncologyPeroxisome Proliferator-Activated ReceptorsPhospholipidsPhosphorylationPre-Clinical ModelPrimary NeoplasmPrognosisReceptor SignalingRecurrenceResearchSerumSignal TransductionSignaling MoleculeSterolsTherapeuticThyroid DiseasesTranslatingTriglyceridesVLDL receptorVery low density lipoproteinWomanaggressive breast cancerbreast cancer diagnosisbreast cancer progressionbreast cancer survivalcancer cellcancer subtypesclinical careclinically translatableepidemiology studyepithelial to mesenchymal transitiongenetic signatureimproved outcomelipidomemalignant breast neoplasmmolecular subtypesmortalitymouse modelneutrophilnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpreclinical studyprogesterone receptor negativerapid growthreceptor expressiontranscriptome sequencingtranscriptomicstriple-negative invasive breast carcinomatumortumor growthtumor hypoxiatumor microenvironmenttumor-immune system interactionsuptakevery 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.
项目摘要/摘要
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)
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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
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{{ 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:
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