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：
7849474
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/7849474
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 Dependence Development Diet Dietary Fats 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 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 Proteins 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 overexpression postnatal programs protein complex 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）：乳腺肿瘤可能通过两种不同的机制获得生长和生存所需的脂肪酸。脂质可以由表达脂肪生成酶的肿瘤细胞从头产生（脂肪生成），这是核蛋白S14支持的过程。或者，细胞外酶脂蛋白脂肪酶（LPL）可以从血液（脂解）中的脂蛋白（脂解）中裂解脂肪酸。乳腺癌细胞不会产生LPL，而是乳腺脂肪垫的脂肪细胞局部供应。然而，在转移过程中，肿瘤细胞会遇到淋巴结和一般循环的环境，这些环境不含LPL，并且必须取决于脂肪生成。我们假设S14 1）促进在乳腺癌转移过程中至关重要的脂质合成能力增强，而2）通过相邻组织提供LPL可促进原发性和转移性乳腺癌的生长，尤其是S14低的乳腺癌和脂肪生成能力。该假设取决于观察到S14在大多数乳腺癌中过表达，S14促进了培养的乳腺癌细胞的生长和存活，S14过表达预测了乳腺癌的复发，乳腺癌细胞不表达LPL。我们的目标集中在鼠乳腺癌模型中S14和LPL的局部可用性以及S14动作机制上的相互作用。具有乳腺上皮特异性S14基因敲除的小鼠将育成原发肿瘤部位（乳腺）和主要转移部位（肺）和MMTV-HER2模型中缺乏LPL的动物。将评估肿瘤发生率，生长，代谢，转移和血管生成。首先，我们将通过比较单独的S14乳腺敲除和组织限制的LPL突变来定义S14和局部LPL的作用。由于饮食脂肪底物将调节LPL改变的影响，因此将评估低脂或高脂饮食的影响。其次，我们将评估强制乳腺S14过表达的影响。第三，我们将鉴定乳腺癌细胞中与S14相互作用的蛋白质，并定义组装S14多聚体的结构要求。这将提供针对乳腺癌中S14的原理证明，确定分子的脆弱点以实现它，并提供一种新颖，全面的肿瘤脂质代谢模型，以考虑脂肪生成，脂解和饮食。 Lay摘要：S14在侵略性的乳腺癌中发现，它促进了其生长所需的脂肪的形成。我们将研究富含高脂饮食的S14的乳腺癌小鼠，其乳腺癌表达高或不存在，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。