Mechanisms of breast cancer associated with obesity

描述（由申请人提供）：在美国，肥胖率正在增加，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，并且这些肿瘤更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，因此已知间质组织微环境对乳腺癌的发展和进展具有深远的影响，肥胖个体的脂肪库内发生的变化可能在乳腺癌的发病机制中起重要作用。因此，阐明脂肪细胞和脂肪组织生物学在乳腺癌中的机制作用对于预防和治疗肥胖相关癌症至关重要。肥胖女性乳腺组织内的脂肪细胞分泌单核细胞趋化蛋白-1（MCP-1），促进巨噬细胞向乳腺脂肪组织的募集。这些细胞在募集时诱导局部组织炎症，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，我们的目标是测试从实验室到人体临床试验，假设肥胖妇女的乳腺组织表现出增加的新血管生成和炎症之前，由于MCP-1产生的脂肪细胞的巨噬细胞的招聘，从而导致增加的血管和恶性肿瘤的明显肿瘤形成。在本项目的目标1中，我们将研究骨髓源性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将测试骨髓源性巨噬细胞是否是肥胖诱导的肿瘤进展所必需的，目标3将确定肥胖诱导的癌前病变是否可以逆转。我们的研究提供了创新的见解，为什么肥胖与癌症发病率和侵袭性增加有关。此外，这项工作将为高危肥胖患者的预防性治疗提供一个新的范例。

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.