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

描述(申请人提供)：本申请的目的是利用饮食诱导的肥胖小鼠乳腺癌模型来生成关于脂肪细胞、乳腺肿瘤细胞和巨噬细胞在乳腺癌发病机制中可能扮演的角色的初步数据。我们的假设是脂肪细胞和乳腺肿瘤细胞可能在巨噬细胞向乳腺的募集中发挥作用，从而导致其致瘤性，这是一个新的假设，因为没有关于这三种细胞类型在乳腺肿瘤微环境中的相互作用的信息。我们将利用小鼠巨噬细胞、乳腺肿瘤和脂肪细胞系的共培养，在体外研究这种细胞相互作用对巨噬细胞趋化、M1/M2激活模式和细胞分化的影响。由脂肪或肿瘤细胞产生的旁分泌因子的特定信号抑制剂将被用来逆转这些作用，并将进行蛋白质组学分析，以确定脂肪细胞和乳腺肿瘤细胞分泌的新分子与巨噬细胞的作用。此外，还将研究阻断这些旁分泌因子的功能对MF‘S NFkB和STAT3激活的影响。我们还将重点介绍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，它在乳腺癌发病机制和巨噬细胞趋化中发挥核心作用。我们其中一人设计的一种新的瘦素信号抑制物肽将用于饮食诱导的肥胖小鼠的体内实验，以逆转移植了同基因C57BL6乳腺肿瘤的动物的原发肿瘤和转移进展以及巨噬细胞募集。我们预计，本提案的结果将最终提供原始信息，为将来在非裔美国人(AA)和拉丁裔(LA)女性中启动类似的乳腺癌研究奠定基础。高脂肪饮食、超重和减少体力活动是AA和LA中常见的增加癌症风险的生活方式方面；这些女性也表现出更具侵袭性的乳腺癌，结果较差。本申请中提出的实验首次解决了乳腺肿瘤内这三种细胞类型之间的相互作用。迫切需要建立研究，以更好地了解不同种族癌症的生物学，并开发工具，以更准确地预测其预后，并设计其个性化的治疗策略。 公共卫生相关性： 建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/受体的表达而促进乳腺癌的理解。这可能为超重/肥胖妇女，特别是非洲裔美国人和拉丁裔妇女，带来预防和/或治疗乳腺癌的新方法，这些妇女的特点是肥胖率/超重率高，乳腺癌侵袭性更强，预后最差。

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.