Altered Lipid Metabolism in Luminal Breast Cancer Stem Cells and Endocrine Resistance

腔内乳腺癌干细胞脂质代谢的改变和内分泌抵抗

• 批准号: 10459264
• 负责人: Ashley Vanessa Ward
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459264
• 关键词: Affect; Biological; Biological Assay; Biology; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; CD44 gene; Cell Line; Cell Separation; Cells; Cessation of life; Characteristics; Complex; Cytokeratin; Data; Dependence; Development; Disease; Disease Resistance; Disease-Free Survival; Endocrine; Enzymes; Estrogen Receptors; Estrogens; Excision; Exhibits; FASN gene; Fatty Acids; Fellowship; Flow Cytometry; Fulvestrant; Funding; Gene Expression Profile; Genetic Transcription; Genus Hippocampus; Goals; Immunohistochemistry; Impairment; In Vitro; Learning; Lecithin; Lipids; Mass Spectrum Analysis; Measures; Mediating; Membrane; Metabolic; Metabolism; Microscopy; Mitochondria; Modeling; Newly Diagnosed; Pathway interactions; Patient Care; Patients; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phenotype; Phospholipids; Population; Prevention; Process; Progesterone Receptors; Progestins; Property; Prostaglandins; Proteins; Recurrence; Relapse; Reporter; Research; Research Personnel; Resistance; Risk; Role; SRE-1 binding protein; Signal Transduction; Stains; Stress Tests; Supplementation; Surface; T47D; Tamoxifen; Techniques; Testing; Tracer; Training; Triglycerides; Withdrawal; base; cancer cell; cancer recurrence; cancer stem cell; chemotherapy; disorder later incidence prevention; estrogen disruption; experience; fatty acid oxidation; fatty acid supplementation; flexibility; hormone therapy; in vivo; knock-down; lipid biosynthesis; lipid metabolism; lipidomics; malignant breast neoplasm; malignant endocrine gland neoplasm; new therapeutic target; overexpression; patient derived xenograft model; prevent; progesterone receptor positive; promoter; receptor expression; refractory cancer; self-renewal; small hairpin RNA; stable isotope; standard of care; stem; stem cell biology; stem cell biomarkers; stem cell expansion; stem cell function; stem cell population; therapeutic target; therapy resistant; transcription factor; tumor; tumor heterogeneity; tumor initiation; tumor metabolism; uptake

Project Summary/Abstract: Over two thirds of newly diagnosed breast cancer patients have estrogen receptor (ER) and progesterone receptor (PR) positive or "luminal" breast cancer. Endocrine therapy is standard of care for these patients and frequently results in long-term disease-free survival or cure. However, one third of luminal breast cancer patients experience recurrence with metastatic and therapy-resistant disease. Recurrence is thought to arise from cancer stem cells (CSCs), a rare subpopulation of cancer cells within a tumor that exhibit stem-like characteristics. These include quiescence, metabolic flexibility, and resistance to endocrine and chemotherapies. These subpopulations are difficult to study in luminal breast cancers due to tumor heterogeneity that is not well understood and, while some tumors contain CD44+ cells, others lack such conventional CSC markers. Our lab has identified that a subpopulation of cytokeratin 5 (CK5)+ cells within luminal breast cancers contain CSC properties including resistance to endocrine and chemotherapies, and increased tumorsphere formation and tumor-initiation relative to CK5− cells. Additionally, we found that the CK5+ subpopulation expands with either progestin treatment or endocrine therapy such as tamoxifen (Tam) or estrogen withdrawal (EWD). CK5+ cells lose ER and PR expression and thus endocrine sensitivity. We used CK5 as a marker for luminal breast cancer CSCs to investigate unique CSC biology and to identify pharmacological targets to prevent disease recurrence for breast cancer patients. Lipidomic analysis of luminal breast cancer cells under EWD or that are Tam-resistant (TamR) revealed a significant loss of triglyceride analytes compared to control T47D cells. In addition, EWD and TamR cells lack visible lipid storage by ORO staining and fail to induce lipid droplet formation with progestins, as typically observed in PR+ luminal breast cancer cell lines. EWD and TamR T47D cells show decreased expression of de novo fatty acid synthesis enzymes, FASN and ACC1, compared to control cells suggesting the lipogenic phenotype typically observed in luminal breast cancer is lost in endocrine resistance. Together, I hypothesize that endocrine resistant luminal breast cancer cells recycle rather than store lipids and this is necessary to maintain CSC function. To test this, I plan on defining the mechanism by which endocrine resistant breast cancer cells shift lipids from storage in Aim 1 and assess the effect of lipid storage on luminal breast CSC function in Aim 2. Understanding CSC lipid biology in breast cancer endocrine resistance is a critical step in identifying therapeutic targets for recurrence prevention.

项目概要/摘要： 超过三分之二的新诊断的乳腺癌患者有雌激素受体（ER）和孕激素 受体（PR）阳性或“管腔”乳腺癌。内分泌治疗是这些患者的标准治疗， 通常导致长期无病生存或治愈。然而，三分之一的管腔乳腺癌患者 经历复发的转移性和治疗抗性疾病。复发被认为是由癌症引起的 干细胞（CSCs）是肿瘤内罕见的癌细胞亚群，表现出干细胞样特征。 这些包括静止，代谢灵活性，对内分泌和化疗的抵抗力。这些 由于肿瘤的异质性， 虽然一些肿瘤含有CD 44+细胞，但其他肿瘤缺乏此类常规CSC标志物。我们实验室 已经鉴定出在管腔型乳腺癌中的细胞角蛋白5（CK 5）+细胞亚群含有CSC， 特性，包括对内分泌和化疗的抗性，以及增加肿瘤球形成， 相对于CK 5 −细胞的肿瘤起始。此外，我们发现CK 5+亚群随着以下两种情况之一而扩大： 雌激素治疗或内分泌治疗，如他莫昔芬（Tam）或雌激素戒断（EWD）。CK 5+细胞 ER和PR表达减少，从而导致内分泌敏感性降低。我们使用CK 5作为管腔型乳腺癌的标志物， CSC研究独特的CSC生物学，并确定预防疾病复发的药理学靶点 for breast乳腺癌patients患者.在EWD下或对TAM耐药的管腔型乳腺癌细胞的脂质组学分析 （TamR）显示与对照T47 D细胞相比甘油三酯分析物的显著损失。此外，EWD和 TamR细胞缺乏通过ORO染色可见的脂质储存，并且不能用孕激素诱导脂滴形成， 如在PR+管腔型乳腺癌细胞系中典型观察到的。EWD和TamR T47 D细胞显示减少的 与对照细胞相比，从头脂肪酸合成酶FXR和ACC 1的表达表明， 典型地在管腔型乳腺癌中观察到的脂肪生成表型在内分泌抗性中丧失。一起我 假设内分泌抗性管腔型乳腺癌细胞循环而不是储存脂质， 以维持CSC的功能。为了验证这一点，我计划定义内分泌抵抗的机制， 乳腺癌细胞转移目标1中储存的脂质，并评估脂质储存对管腔乳腺CSC的影响 目标2中的功能。了解CSC脂质生物学在乳腺癌内分泌抵抗中的作用是研究CSC的关键一步。 确定预防复发的治疗靶点。