Mechanisms of breast cancer associated with obesity

乳腺癌与肥胖相关的机制

基本信息

批准号：
9116543
负责人：
CHARLOTTE KUPERWASSER
金额：
$ 8.74万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116543
关键词：
Accounting Adipocytes Adipose tissue African American Aggressive behavior Biology Body Weight decreased Body mass index Bone Marrow Breast Breast Diseases Cells Cessation of life Clinical Trials Communities Complex Development Diagnosis Diet Distant Enrollment Environment Estrogen receptor negative Estrogen receptor positive Estrogens Exercise Exhibits Fatty acid glycerol esters Health High Risk Woman Hormonal Human ITGAM gene Incidence Individual Inflammation Intervention Investigator-Initiated Research Lesion Link Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Modeling Molecular Mus Neoplasm Metastasis Nodal Obesity Obesity associated cancer Operative Surgical Procedures Pathogenesis Patients Play Pre-Clinical Model Premalignant Premenopause Preneoplastic Change Preventable cancer cause Prevention Production Prophylactic treatment Proteins Recruitment Activity Recurrence Relative (related person)Research Project Grants Risk Role Stromal Cells Stromal Change Testing Tissues Transgenic Model Tumor Angiogenesis United States Woman Work angiogenesis bariatric surgery base cancer initiation cancer risk caucasian American clinically relevant cohort high risk in vivo inhibitor/antagonist innovation insight lymph nodes macrophage malignant breast neoplasm monocyte mouse model novel prospective response small molecule subcutaneous tumor tumor progression

项目摘要

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.

描述（由申请人提供）：在美国，肥胖率正在增加，并且了解与肥胖相关的乳腺癌的分子和细胞基础具有显着的临床相关性和影响。肥胖女性比瘦女性更有可能被诊断为非家庭雌激素受体阴性肿瘤，并且这些肿瘤更有可能与淋巴结转移有关。由于乳腺基质组织是皮下脂肪的水库，因此已知基质组织微环境对乳腺癌的发育和进展产生深远的影响，因此在肥胖个体的脂肪库中发生的变化可能在乳腺癌的发病机理中起重要作用。因此，阐明脂肪细胞和脂肪组织生物学在乳腺癌中的机理作用对于预防和治疗与肥胖相关的癌症至关重要。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），该蛋白1（MCP-1）促进巨噬细胞募集到乳腺脂肪组织中。这些细胞招募时会诱导局部组织炎症，但是巨噬细胞在与肥胖相关的炎症中的作用目前尚不清楚。在这里，我们旨在测试从长凳到人类临床试验，肥胖女性乳腺组织在明显的肿瘤形成之前表现出增加的新血管生成和炎症，这是由于MCP-1通过产生脂肪细胞募集的巨噬细胞而导致的，从而导致血管性和恶性增加。在该项目的AIM 1中，我们将研究骨髓衍生的巨噬细胞促进肥胖引起的血管生成和癌症起源的分子机制。 AIM 2将测试骨髓衍生的巨噬细胞是否对于肥胖诱导的肿瘤进展是必要的，AIM 3将决定是否可以逆转肥胖诱导的前塑性变化。我们的研究提供了创新的见解，说明为什么肥胖与癌症发病率增加和侵略性有关。此外，这项工作将为高风险肥胖患者的预防治疗提供新的范式。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigenetic Dysregulation of KCNK9 Imprinting and Triple-Negative Breast Cancer.

DOI：
10.3390/cancers13236031
发表时间：
2021-11-30
期刊：
Cancers
影响因子：
5.2
作者：
Skaar DA;Dietze EC;Alva-Ornelas JA;Ann D;Schones DE;Hyslop T;Sistrunk C;Zalles C;Ambrose A;Kennedy K;Idassi O;Miranda Carboni G;Gould MN;Jirtle RL;Seewaldt VL
通讯作者：
Seewaldt VL