Mechanisms of breast cancer associated with obesity

描述(申请人提供)：在美国，肥胖率正在上升，了解与肥胖相关的乳腺癌的分子和细胞基础具有重要的临床相关性和影响。肥胖女性比瘦女性更容易被诊断为非家族性雌激素受体阴性肿瘤，而且这些肿瘤更有可能与淋巴结转移有关。由于乳腺间质组织是皮下脂肪的储存库，间质组织微环境对乳腺癌的发生和发展具有深远的影响，肥胖者脂肪储存库内发生的变化可能在乳腺癌的发病机制中发挥重要作用。因此，阐明脂肪细胞和脂肪组织生物学在乳腺癌中的作用机制对于预防和治疗肥胖相关癌症至关重要。肥胖女性乳房组织中的脂肪细胞分泌一种单核细胞化学吸引蛋白-1(MCP-1)，促进巨噬细胞向乳房脂肪组织募集。当这些细胞被招募时，会引起局部组织炎症，但巨噬细胞在肥胖相关炎症中的作用目前尚不清楚。在这里，我们的目标是从试验台到人类临床试验，假设肥胖女性的乳房组织在明显的肿瘤形成之前表现出更多的新血管生成和炎症，这是由于产生MCP-1的脂肪细胞募集巨噬细胞，从而导致血管增加和恶性肿瘤。在本项目的目标1中，我们将研究骨髓来源的巨噬细胞促进肥胖诱导的血管生成和癌症发生的分子机制。目标2将测试骨髓来源的巨噬细胞是否对肥胖诱导的肿瘤进展是必要的，目标3将确定肥胖诱导的癌前病变是否可以逆转。我们的研究为为什么肥胖与癌症发病率和侵袭性的增加有关提供了创新的见解。此外，本研究还将为高危肥胖患者的预防性治疗提供一种新的范式。

DESCRIPTION (provided by applicant): In the United States obesity rates are increasing, and understanding the molecular and cellular basis for breast cancer associated with obesity is of significant clinical relevance and impact. Obese women are more likely to be diagnosed with non-familial estrogen receptor negative tumors than lean women, and these tumors are more likely to be associated with nodal metastases. Since breast stromal tissue is a reservoir of subcutaneous fat the stromal tissue microenvironment is known to have a profound effects on breast cancer development and progression, the changes that take place within the fat depots of obese individuals may play a significant role in the pathogenesis of breast cancer. Therefore, elucidating the mechanistic role of adipocytes and adipose tissue biology in breast cancer is critical for prevention and treatment of obesity-related cancer. Fat cells within the breast tissue of obese women secrete a monocyte chemo-attractant protein-1 (MCP-1) that promotes the recruitment of macrophages into breast adipose tissue. These cells when recruited induce local tissue inflammation, but role of macrophages in obesity-associated inflammation during is currently unknown. Here, we aim to test from bench to human clinical trials, the hypothesis that breast tissue in obese women exhibits increased neoangiogenesis and inflammation prior to overt tumor formation due to the recruitment of macrophages by MCP-1 producing adipocytes, thereby leading to increased vascularity and malignancy. In Aim 1 of this project, we will investigate the molecular mechanism by which bone marrow-derived macrophages promote obesity-induced angiogenesis and cancer initiation. Aim 2 will test whether bone marrow-derived macrophages are necessary for obesity-induced tumor progression, and Aim 3 will determine whether obesity-induced preneoplastic changes can be reversed. Our studies provide innovative insight as to why obesity is associated with increased cancer incidence and aggressiveness. In addition, this work will provide a novel paradigm for the prophylactic treatment of high risk obese patients.