Role of Protein S14 in Normal and Neoplastic Mammary Gland

蛋白质 S14 在正常和肿瘤乳腺中的作用

基本信息

批准号：
7319228
负责人：
WILLIAM B KINLAW
金额：
$ 25.28万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-12-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7319228
关键词：
Accounting Address Adipocytes Animals Binding Biochemical Biology Blood Blood Circulation Breast Cancer Cell Breast Cancer Model Breeding Cancer Cell Growth Cancer Patient Cleaved cell Complement Complex Condition Dependence Development Diet Dietary Fats Disruption Environment Enzymes Epithelial Epithelial Cells Fat-Restricted Diet Fatty Acids Fatty acid glycerol esters Female Genes Growth Human Incidence Knock-out Knowledge Left Lipids Lipolysis Lipoproteins Localized Lung Mammary Neoplasms Mammary gland Mediating Metabolism Minnesota Modeling Mouse Mammary Tumor Virus Mus Mutation Neoplasm Metastasis Nuclear Protein Nuclear Proteins Oocytes Primary Neoplasm Process Protein Overexpression Proteins Rate Research Personnel Rest Role Signal Transduction Site Therapeutic Tissues Transgenes Virulence Work angiogenesis cancer recurrence defined contribution extracellular feeding in vivo Model knockout gene lipid biosynthesis lipid metabolism lipoprotein lipase lymph nodes malignant breast neoplasm mouse model mutant neoplastic neoplastic cell novel postnatal programs research study saturated fat spot 14 protein tissue culture tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast tumors may obtain the fatty acids they require for growth and survival by two distinct mechanisms. Lipids may be produced de novo (lipogenesis) by tumor cells that express lipogenic enzymes, a process supported by nuclear protein S14. Alternatively, fatty acids may be cleaved from lipoproteins in the blood (lipolysis) by the extracellular enzyme lipoprotein lipase (LPL). Breast cancer cells do not make LPL, but adipocytes of the mammary fat pad supply it locally. During metastasis, however, tumor cells encounter environments such as lymph node and the general circulation that are devoid of LPL, and must depend on lipogenesis. We hypothesize that S14 1) promotes enhanced lipid synthesizing capacity that is crucial during breast cancer metastasis, and 2) that provision of LPL by adjacent tissue promotes growth of primary and metastatic breast cancers, particularly those with low S14 and lipogenic capacity. The hypothesis rests on observations that S14 is overexpressed in most breast cancers, S14 drives growth and survival of cultured breast cancer cells, S14 overexpression predicts breast cancer recurrence, and breast cancer cells do not express LPL. Our Aims focus on interactions of S14 and local availability of LPL in a murine breast cancer model, and on mechanisms of S14 action. Mice with mammary epithelial-specific S14 gene knockout will be bred with animals lacking LPL in the primary tumor site (mammary gland) and the major metastatic site (lung), and the MMTV-Her2 model. Tumor incidence, growth, metabolism, metastasis, and angiogenesis will be assessed. First we will define the roles of S14 and local LPL by comparing the S14 mammary knockout and tissue-restricted LPL mutations alone and together in the Her2 model. As dietary fat substrate will condition the impact of altered LPL, effects of low- or high-fat diets will be assessed. Second, we will assess the impact of enforced mammary S14 overexpression. Third, we will identify proteins that interact with S14 in breast cancer cells, and define structural requirements for assembly of S14 multimers. This will provide proof of principle for targeting S14 in breast cancer, identify vulnerable points of the molecule to achieve it, and provide a novel, comprehensive model of tumor lipid metabolism that takes lipogenesis, lipolysis, and diet into account. Lay Summary: S14 is found in aggressive breast cancers, where it promotes formation of fats they require for growth. We will study breast cancer-prone mice with high or absent mammary expression of S14 fed high and low fat diets, and will also use a biochemical approach to determine how S14 works. This work will pave the way for anti-S14 treatments for breast cancer patients.

描述（由申请人提供）：乳腺肿瘤可以通过两种不同的机制获得生长和存活所需的脂肪酸。脂质可由表达脂肪生成酶的肿瘤细胞从头产生（脂肪生成），这一过程由核蛋白 S14 支持。或者，脂肪酸可以通过细胞外酶脂蛋白脂肪酶（LPL）从血液中的脂蛋白上裂解（脂解）。乳腺癌细胞不产生 LPL，但乳腺脂肪垫的脂肪细胞在局部提供 LPL。然而，在转移过程中，肿瘤细胞会遇到缺乏LPL的环境，例如淋巴结和体循环，并且必须依赖于脂肪生成。我们假设 S14 1) 促进脂质合成能力增强，这在乳腺癌转移过程中至关重要，2) 邻近组织提供的 LPL 促进原发性和转移性乳腺癌的生长，特别是那些 S14 和脂肪生成能力低的乳腺癌。该假设基于以下观察结果：S14 在大多数乳腺癌中过度表达，S14 促进培养的乳腺癌细胞的生长和存活，S14 过度表达预测乳腺癌复发，而乳腺癌细胞不表达 LPL。我们的目标集中于小鼠乳腺癌模型中 S14 和 LPL 局部可用性的相互作用，以及 S14 的作用机制。乳腺上皮特异性 S14 基因敲除的小鼠将与原发肿瘤部位（乳腺）和主要转移部位（肺）缺乏 LPL 的动物以及 MMTV-Her2 模型进行繁殖。将评估肿瘤的发生、生长、代谢、转移和血管生成。首先，我们将通过比较 Her2 模型中单独和一起比较 S14 乳腺敲除和组织限制性 LPL 突变来定义 S14 和局部 LPL 的作用。由于膳食脂肪底物会影响 LPL 改变的影响，因此将评估低脂肪或高脂肪饮食的影响。其次，我们将评估强制乳房 S14 过度表达的影响。第三，我们将鉴定乳腺癌细胞中与 S14 相互作用的蛋白质，并确定 S14 多聚体组装的结构要求。这将为乳腺癌中的 S14 靶向提供原理证明，确定该分子的脆弱点以实现这一目标，并提供一种新颖、全面的肿瘤脂质代谢模型，将脂肪生成、脂肪分解和饮食考虑在内。摘要：S14 存在于侵袭性乳腺癌中，它能促进生长所需脂肪的形成。我们将研究喂食高脂肪和低脂肪饮食的乳腺 S14 表达高或缺失的易患乳腺癌的小鼠，并且还将使用生化方法来确定 S14 的工作原理。这项工作将为乳腺癌患者的抗 S14 治疗铺平道路。