Role of obesity and breast fat tissue inflammation in breast cancer promotion.

描述（由申请人提供）：本申请的目的是生成关于局部乳腺脂肪组织在肥胖/超重条件下乳腺癌进展中可能具有的合理作用的初始数据。为此，我们将使用饮食诱导的肥胖小鼠乳腺癌模型。这项工作是我们正在进行的NIH资助工作的自然补充和延伸。 大多数将肥胖与癌症联系起来的研究都集中在肥胖的全身效应上。特别是在乳腺癌中，很少有人关注肥胖是否也通过其对乳腺中局部脂肪组织炎症和先天免疫信号的影响促进这种疾病-癌症发生的地方。我们提出，在肥胖/超重的情况下，乳房中的局部脂肪组织变得炎症性，并在很大程度上通过招募大量的促肿瘤炎性巨噬细胞到乳房肿瘤微环境来促进癌症的发展。 我们将使用一个创新的实验设计来检验我们的假设在饮食诱导的肥胖小鼠。我们将使用另外两个众所周知的脂肪库作为参考来衡量乳房脂肪组织促进肿瘤发展的能力：内脏和皮下脂肪库，它们分别表现出高度和低度的炎症。为此，我们将分析肿瘤进展，巨噬细胞募集和肿瘤中炎症分子的产生，这些炎症分子是由植入这些脂肪部位的肿瘤细胞引起的。最后，我们将使用一种新的化合物，它属于我们团队发现的一个新的小分子家族。这些分子-称为白细胞粘附素-通过激活Mac-1整联蛋白减少炎症。 我们将在体内环境中使用最有效的白细胞粘附素Leukadherin-1（LA-1）来检查其对肿瘤进展和巨噬细胞募集的影响。 为此，我们将用增加剂量的这种化合物治疗肥胖和瘦的荷瘤小鼠。此外，我们将在体外用不同浓度的LA-1预处理巨噬细胞，以确定该化合物是否调节巨噬细胞的炎症信号通路和炎症分子的表达。我们设想，本提案的结果将使我们能够揭示局部乳腺癌的作用的存在。 肥胖症及其相关分子。重要的是，我们的工作也将作为评估这些新型抗炎化合物在乳腺癌控制中的作用的手段。高脂肪饮食，超重和减少体力活动是非洲裔美国人和拉丁美洲妇女中常见的生活方式方面，这些生活方式增加了癌症风险-这些少数民族妇女也表现出更具侵略性的乳腺癌，预后较差。本申请中提出的实验以创新的方式解决了乳腺脂肪组织炎症的性质和控制及其在肥胖中的乳腺癌中的影响。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，更准确地预测其预后并设计定制的治疗策略。

DESCRIPTION (provided by applicant): The purpose of the present application is to generate the initial data on the plausible role that local breast adipose tissue may have in breast cancer progression in conditions of obesity/overweight. To do this, we will use diet-induced obesity mouse models of breast cancer. This work is a natural complement and extension of our ongoing NIH-funded work. Most studies linking obesity and cancer have focused on the systemic effects of adiposity. Particularly in breast cancer, little attention has been paid to whether obesity also promotes this disease through its effect on local adipose tissue inflammation and innate immune signaling in the breast- where cancer occurs. We propose that in conditions of obesity/overweight the local adipose tissue in the breast becomes inflammatory and contributes to cancer development in great part by recruiting larger numbers of tumor-promoting inflammatory macrophages to the breast tumor microenvironment. We will use an innovative experimental design to examine our hypothesis in diet-induced obese mice. We will gauge breast adipose tissue's capacity to promote tumor development using two other well-known fat depots as reference: visceral and subcutaneous fat depots, which exhibit high and low degrees of inflammation, respectively. To do this, we will analyze tumor progression, macrophage recruitment and production of inflammatory molecules in tumors arising from tumor cells implanted on these fat locations. Finally, we will use a novel compound belonging to a new family of small molecules discovered by our team. These molecules - termed leukadherins - reduce inflammation via activation of Mac-1 integrin. We will use Leukadherin-1 (LA-1), the most potent of the leukadherins, in an in vivo setting to examine its impact on tumor progression and macrophage recruitment. For this, we will treat obese and lean tumor-bearing mice with increasing doses of this compound. Also, we will in vitro pre-treat macrophages with different concentrations of LA-1 to determine whether this compound modulates macrophage's inflammatory signaling pathways and expression of inflammatory molecules. We envision that results from the present proposal will enable us to reveal the existence of a role for local breast adiposity and related molecules in obesity. Importantly, our work will also serve as means to assess the effect of these novel anti-inflammatory compounds in the control of breast cancer. A high-fat diet, overweight and reduced physical activity are common lifestyle aspects among African American and Latina women that increase cancer risk~ these minority women also exhibit more aggressive breast cancers with less favorable prognosis. The experiments proposed in this application address in an innovative fashion the nature and control of breast adipose tissue inflammation and its impact in breast cancer within obesity. There is an urgent need to build up studies to better understand the biology of cancers across ethnicities, and to develop tools that will more accurately predict their prognosis and design their customized treatment strategies.