Breast cancer health disparity:mammary fat tissue and tumor macrophages interpla

乳腺癌健康差异：乳腺脂肪组织与肿瘤巨噬细胞间质

基本信息

批准号：
8100038
负责人：
MARTA TORROELLA-KOURI
金额：
$ 20.86万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-04 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8100038
关键词：
A Mouse Address Adipocytes Adipose tissue Affect African American Animals Aromatase Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Breast Cancer Treatment CCAAT-Enhancer-Binding Proteins CCL2 gene Cancer Biology Cancer Patient Cancer and Nutrition Caucasians Caucasoid Race Cell Differentiation process Cell Line Cell physiology Cells Chemotaxis Coculture Techniques Collaborations Data Development Diet Dinoprostone Estrogens Ethnic Origin Ethnic group Exhibits Fatty Acids Fatty acid glycerol esters Foundations Future Genetic Goals High Prevalence Historically Black Colleges and Universities Hormones Human Immune Implant In Vitro Individual Inflammatory Institution Investigation Latina Lauric Acids Lead Leptin Life Style Ligands Macrophage Activation Malignant Neoplasms Mammary Neoplasms Mammary gland Methods Minority Modeling Molecular Mouse Cell Line Mus Neoplasm Metastasis Obese Mice Obesity Outcome Overweight Paracrine Communication Pathogenesis Patients Peptides Peritoneal Physical activity Play Preparation Primary Neoplasm Proteomics Reagent Recruitment Activity Research Research Personnel Role STAT1 gene STAT3 gene Signal Transduction Signaling Molecule Testing Therapeutic Time Tissues Tumor Biology Tumor Tissue Tumorigenicity Woman Work Xenograft procedure adipokines anticancer research base cancer cell cancer health disparity cancer initiation cancer risk cell type chemokine design in vitro testing in vivo inhibitor/antagonist innovation macrophage malignant breast neoplasm mortality mouse model neoplastic cell novel novel strategies outcome forecast paracrine receptor research study socioeconomics tool transcription factor treatment strategy tumor tumor initiation tumor progression

项目摘要

DESCRIPTION (provided by applicant): The purpose of the present application is to generate the initial preliminary data using diet-induced obesity mouse models of breast cancer on the plausible roles of adipocytes, mammary tumor cells and macrophages in breast cancer pathogenesis. Our hypothesis that adipocytes and mammary tumor cells may play a role in the recruitment of macrophages to the mammary gland contributing to its tumorigenicity is novel, since there is no information regarding the crosstalk between these three cell types in the mammary tumor microenvironment. We will examine the impact of this cellular interplay on macrophage chemotaxis, M1/M2 activation profiles and cell differentiation in vitro, using co-cultures of mouse macrophage, mammary tumor and adipocyte cell lines. Specific signaling inhibitors of paracrine factors produced by adipose or tumor cells will be used to reverse these actions, and proteomics analyses will be undertaken to identify novel molecules secreted by adipocytes and mammary tumor cells with actions on macrophages. Moreover, the impact of blocking the functions of these paracrine factors on mf 's NFkB and STAT3 activation will be studied.. We will also focus on one of these paracrine factors, the adipokine leptin, produced by adipocytes and mammary tumor cells, which has a central role in breast cancer pathogenesis and in macrophage chemotaxis. A novel leptin-signaling inhibitor peptide designed by one of us will be used in in vivo experiments with diet-induced obese mice to reverse primary tumor and metastasis progression and macrophage recruitment in these animals implanted with syngeneic C57BL6 mammary tumors. We envision that results from the present proposal will ultimately provide original information that will lay the foundation to initiate similar studies in breast cancer in African American (AA) and Latina (LA) women in the future. A high-fat diet, overweight and reduced physical activity are common lifestyle aspects among AA and LA that increase cancer risk; these women also exhibit more aggressive breast cancers with less favorable outcomes. The experiments proposed in this application address for the first time the interaction between these three cell types within breast tumors. There is an urgent need to build up studies to better understand the biology of cancers across ethnicities, and to develop tools to more accurately predict their prognosis and design their customized treatment strategies. PUBLIC HEALTH RELEVANCE: The proposed studies will increase our understanding on how the actions of adipose tissue on the mammary gland may promote breast cancer through macrophage recruitment and expression of important ligands/receptors. This could lead to new ways of breast cancer prevention and/or therapeutic alternatives for overweight/obese women, especially African American and Latinas, characterized by high prevalence of obesity/overweight and more aggressive breast cancers with worst prognoses.

描述（由申请人提供）：本申请的目的是使用饮食诱导的乳腺癌肥胖小鼠模型在脂肪细胞，乳腺肿瘤细胞和巨噬细胞的合理作用上生成初始的初步数据。我们的假设是，脂肪细胞和乳腺肿瘤细胞可能在巨噬细胞募集到乳腺中起作用，从而导致其肿瘤性，这是新颖的，因为在乳腺肿瘤微环境中这三种细胞类型之间没有有关串扰的信息。我们将使用小鼠巨噬细胞，乳腺肿瘤和脂肪细胞系的共培养来研究这种细胞相互作用对巨噬细胞趋化性，M1/M2激活谱和细胞分化的影响。脂肪或肿瘤细胞产生的旁分泌因子的特定信号抑制剂将用于扭转这些作用，并将进行蛋白质组学分析，以鉴定脂肪细胞和乳腺肿瘤细胞分泌的新分子，并具有对巨噬细胞作用的作用。此外，将研究阻止这些旁分泌因子对MF的NFKB和STAT3激活的功能的影响。.我们还将重点关注这些旁分泌因子之一，脂肪细胞和乳腺肿瘤细胞产生的脂肪因子瘦素，这在乳腺癌病原体和乳腺癌中具有中心作用。由我们中的一个人设计的新型瘦素信号抑制剂肽将用于饮食诱导的肥胖小鼠的体内实验，以逆转原发性肿瘤，转移和转移进展和巨噬细胞募集，这些动物植入了同步的C57BL6乳腺肿瘤。我们设想，本提案的结果最终将提供原始信息，从而为非裔美国人（AA）和Latina（LAINA）妇女启动类似的乳腺癌研究奠定基础。高脂饮食，超重和体育锻炼减少是AA和LA之间的常见生活方式方面，增加了癌症风险；这些妇女还表现出更具侵略性的乳腺癌，结果较差。该应用程序地址中提出的实验首次在乳腺肿瘤中这三种细胞类型之间的相互作用。迫切需要建立研究以更好地了解跨种族的癌症的生物学，并开发工具以更准确地预测其预后并设计其定制的治疗策略。公共卫生相关性：拟议的研究将增加我们对脂肪组织对乳腺的作用如何通过巨噬细胞募集和重要配体/受体表达促进乳腺癌的理解。这可能会导致预防乳腺癌的新方法和/或用于超重/肥胖女性，尤其是非裔美国人和拉丁裔的治疗替代方法，其特征是肥胖/超重和更具侵略性的乳腺癌患病率更高。