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

描述（由申请人提供）：本申请的目的是利用饮食诱导的乳腺癌肥胖小鼠模型生成初步数据，探讨脂肪细胞、乳腺肿瘤细胞和巨噬细胞在乳腺癌发病机制中的可能作用。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，从而促进其致瘤性，这一假设是新颖的，因为没有关于这三种细胞类型在乳腺肿瘤微环境中相互作用的信息。我们将研究这种细胞相互作用对巨噬细胞趋化性、M1/M2激活谱和体外细胞分化的影响，使用小鼠巨噬细胞、乳腺肿瘤和脂肪细胞系共培养。脂肪细胞或肿瘤细胞产生的旁分泌因子的特异性信号抑制剂将用于逆转这些作用，蛋白质组学分析将用于鉴定脂肪细胞和乳腺肿瘤细胞分泌的对巨噬细胞起作用的新分子。此外，我们还将研究阻断这些旁分泌因子的功能对mf的NFkB和STAT3激活的影响。我们还将关注其中一种旁分泌因子，脂肪因子瘦素，由脂肪细胞和乳腺肿瘤细胞产生，在乳腺癌发病机制和巨噬细胞趋化中起核心作用。我们设计的一种新型瘦素信号抑制肽将用于饮食诱导的肥胖小鼠体内实验，以逆转这些动物植入同源C57BL6乳腺肿瘤的原发肿瘤和转移进展以及巨噬细胞募集。我们设想，本提案的结果将最终提供原始信息，为将来在非洲裔美国人（AA）和拉丁裔（LA）妇女中开展类似的乳腺癌研究奠定基础。高脂肪饮食、超重和减少体育活动是AA和LA人群中常见的增加癌症风险的生活方式；这些女性还表现出更具侵袭性的乳腺癌，其预后较差。本应用程序中提出的实验首次涉及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，以更好地了解不同种族的癌症生物学，并开发工具，以更准确地预测他们的预后，并设计他们的定制治疗策略。

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.