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在肥胖/超重的情况下局部乳房脂肪组织在乳腺癌进展中可能起到的可能作用的初始数据。为了做到这一点，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。大多数将肥胖和癌症联系起来的研究都集中在肥胖症的全身影响上。尤其是在乳腺癌中，肥胖是否也会通过影响乳房局部脂肪组织炎症和先天性免疫信号来促进这种疾病，这一点几乎没有引起注意。我们认为，在肥胖/超重的情况下，乳腺局部脂肪组织变得炎性，并在很大程度上通过招募大量促进肿瘤的炎性巨噬细胞到乳腺肿瘤微环境而促进癌症的发展。我们将使用一种创新的实验设计来检验我们在饮食诱导的肥胖小鼠中的假设。我们将以另外两个著名的脂肪储存库为参考来衡量乳房脂肪组织促进肿瘤发展的能力：内脏脂肪储存库和皮下脂肪储存库，这两个脂肪库分别显示出高和低程度的炎症。为此，我们将分析肿瘤进展、巨噬细胞募集和肿瘤中炎性分子的产生，这些炎症分子是由移植到这些脂肪位置的肿瘤细胞产生的。最后，我们将使用一种新的化合物，属于我们团队发现的一种新的小分子家族。这些分子被称为白细胞粘附素，通过激活Mac-1整合素来减少炎症。我们将在活体环境中使用最有效的白细胞粘附素-1(LA-1)来检测其对肿瘤进展和巨噬细胞募集的影响。为此，我们将通过增加这种化合物的剂量来治疗肥胖和瘦荷瘤小鼠。此外，我们将在体外用不同浓度的LA-1对巨噬细胞进行预处理，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。我们预计，本提案的结果将使我们能够揭示局部乳房存在的作用 肥胖与肥胖及其相关分子的关系。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控制乳腺癌方面的效果的手段。高脂肪饮食、超重和减少体力活动是非裔美国人和拉丁裔女性常见的生活方式方面，会增加患癌症的风险。这些少数族裔女性也表现出更具侵袭性的乳腺癌，预后较差。本申请中提出的实验以一种创新的方式解决了乳房脂肪组织炎症的性质和控制及其对肥胖乳腺癌的影响。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，更准确地预测癌症的预后，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.