Palmitic Acid and Basal-like Breast Cancer Progression

棕榈酸和基底样乳腺癌进展

• 批准号: 10046276
• 负责人: Qun Zhou
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046276
• 关键词: Animals; Architecture; Automobile Driving; Basement membrane; Behavioral; Breast; Breast Cancer Cell; Cell Differentiation process; Cell physiology; Cells; Chemoprevention; Clinical; Color; Data; Development; Diagnosis; Dietary Factors; Drug Delivery Systems; Drug Kinetics; Duct (organ) structure; ERBB2 gene; Enzymes; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Estrogen Receptor alpha; Event; Extracellular Matrix; Feasibility Studies; Female; Foundations; Genetic; Glucosides; Goals; Human; Impairment; Incidence; Intake; LIPG gene; Lobular; Luteolin; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mesenchymal; Metabolism; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Methodology; Methods; Molecular; Molecular Target; Myoepithelial; Myoepithelial cell; Myoepithelioma; Neoplasm Circulating Cells; Neoplasm Metastasis; Newly Diagnosed; Palmitic Acids; Patients; Phenotype; Plants; Progesterone Receptors; Public Health; Puerto Rico; Reporter; Risk Factors; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Taraxacum; Testing; Tissues; Toxic effect; Translating; Tumor Cell Invasion; Tumor Suppressor Proteins; United States; Veterans; Veterans Health Administration; Woman; Work; base; breast cancer diagnosis; breast cancer progression; cancer cell; cancer stem cell; clinically relevant; combat; design; drug discovery; hormone therapy; infiltrating duct carcinoma; inhibitor/antagonist; malignant breast neoplasm; mammary; mammary epithelium; military veteran; mortality; mouse model; nanoparticle; neoplastic cell; new technology; novel; novel chemoprevention; patient population; prevent; progesterone receptor A; promoter; receptor; restoration; screening; stem-like cell; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; western diet

Background/Rationale: It is estimated that approximately 316,000 women will be newly diagnosed with breast cancer in the United States (U.S.) each year, and 40,000 women will die of breast cancer this year alone. Basal-like breast cancer accounts for 15-20% of all diagnosed breast cancer depending on patient population. These patients are commonly known as triple negative breast cancer because most cases often lack expression of estrogen receptor α (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The absence of PR, ERa, and HER-2 commonly found in basal-like breast cancer leads to these patients unlikely to respond to hormone therapies or HER-2 targeted therapies. Thus, basal-like breast cancer is highly aggressive, and often results in lung and brain metastasis. Understanding risk factors for basal-like breast cancer invasion and metastasis is urgently needed for identification of novel and specific molecular targets. Because women represent the fastest growing demographic in the US Veteran population, breast cancer is an increasingly significant public health issue for the Veterans Health Administration. Our proposed studies will investigate the transition from early-stage basal-like breast cancer to invasive breast cancer. Objectives: Palmitic acid is one of the predominant saturated fatty acids in the western diet. The goal of this study is to determine how high-palmitic acid (HPA) intake acts as a risk factor to facilitate basal-like breast cancer invasion. Based on our preliminary studies, we hypothesize that HPA increases the endothelial lipase ( LIPG) activity, which is a key driver of invasive progression in early-stage basal-like breast cancer. We also hypothesize that HPA initiates defective myoepithelial cell differentiation or loss of the mature myoepithelium, which allows tumor cell invasion. Methods: Specific Aim 1 will examine how HPA converts quiescent LIPG-negative tumor cells into LIPG-positive tumor-initiating cells for early-stage basal-like breast cancer invasion. Specific Aim 2 will investigate how LIPG signaling pathways contribute to loss of normal myoepithelial cell function in HPA conditions. We have initiated studies screening natural compounds combined with computational drug discovery approaches, and identified a potent LIPG inhibitor DDL-1. Specific Aim 3 will determine if inhibition of LIPG prevents early-stage basal-like breast cancer to invasive breast cancer progression in HPA conditions. We have developed a new nanoparticle-based drug delivery system to deliver DDL-1 into mammary myoepithelial cells and tumor cells. We will use mouse models of early-stage basal-like breast cancer to study the effect of DDL-1 administration on the incidence of invasive breast cancer and circulating tumor cells in HPA conditions. Results: By identifying a mechanism by which breast cancer invasion occurs, we are hopeful that we can design a novel chemoprevention solution to inhibit tumor invasion, and therefore reduce the number of Veterans dying of advanced or metastatic breast cancer.

背景/理由：据估计，约有316 000名妇女将在2010年 美国乳腺癌的诊断（美国）每年有4万名女性 今年死于乳腺癌基底样乳腺癌占所有乳腺癌的15-20%， 乳腺癌的诊断取决于患者人群。这些患者通常 三阴性乳腺癌，因为大多数病例通常缺乏 雌激素受体α（ER）、孕激素受体（PR）和人表皮生长因子 受体2（HER-2）。基底样细胞中常见的PR、ERa和HER-2的缺失 乳腺癌导致这些患者不太可能对激素治疗或HER-2反应 靶向治疗。因此，基底细胞样乳腺癌是高度侵袭性的，并且经常导致 肺和脑转移。了解基底细胞样乳腺癌侵袭的风险因素 并且转移迫切需要鉴定新的和特异性的分子靶标。 因为女性是美国退伍军人中增长最快的群体， 乳腺癌是退伍军人健康的一个日益重要的公共卫生问题 局我们提出的研究将调查从早期的基底样的过渡 乳腺癌到浸润性乳腺癌。 目的：棕榈酸是西方饮食中主要的饱和脂肪酸之一。 这项研究的目的是确定高棕榈酸（HPA）摄入量如何作为一个风险 促进基底细胞样乳腺癌侵袭的因子。根据我们的初步研究， 假设HPA增加内皮脂酶（LIPG）活性，这是一个关键驱动因素 早期基底细胞样乳腺癌的侵袭性进展。我们还假设， HPA启动缺陷性肌上皮细胞分化或成熟肌上皮的丧失， 从而允许肿瘤细胞侵入。 方法：特异性目的1将检查HPA如何转化静止的LIPG阴性肿瘤 细胞转化为LIPG阳性肿瘤起始细胞，用于早期基底样乳腺癌侵袭。 具体目标2将研究LIPG信号通路如何导致正常丧失 HPA条件下的肌上皮细胞功能。我们已经开始研究筛选天然的 化合物与计算药物发现方法相结合，并确定了一种有效的 LIPG抑制剂DDL-1。具体目标3将确定LIPG的抑制是否可防止早期 HPA条件下基底样乳腺癌向浸润性乳腺癌进展。我们有 开发了一种新的基于纳米颗粒的药物递送系统，将EST-I递送到乳腺 肌上皮细胞和肿瘤细胞。我们将使用早期基底样乳腺的小鼠模型 癌症研究的影响，在浸润性乳腺癌的发病率的ESTA-1管理 和循环肿瘤细胞。 结果：通过确定乳腺癌侵袭发生的机制，我们有希望 我们可以设计一种新的化学预防方案来抑制肿瘤的侵袭， 减少死于晚期或转移性乳腺癌的退伍军人人数。