Obesity, body fat distribution, and breast cancer risk: is visceral fat the culprit after menopause?

肥胖、身体脂肪分布和乳腺癌风险：内脏脂肪是绝经后的罪魁祸首吗？

基本信息

批准号：
10586626
负责人：
Erin Giles
金额：
$ 49.13万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586626
关键词：
Abdomen Acceleration Adipose tissue Biological Body Composition Body Weight Body Weight decreased Body fat Breast Breast Cancer Risk Factor Chronic Clinical Data Coculture Techniques Data Deposition Development Distant Estrogens Fatty acid glycerol esters Future Goals Grant Growth Factor Growth and Development function Hip region structure Hormone Receptor Hormones In Vitro Incidence Infiltration Inflammation Inflammatory Insulin Resistance Intervention Knowledge Life Link Lipectomy Macrophage Macrophage Activation Malignant Neoplasms Mammary Neoplasms Measurable Mediating Menopause Metabolic Metabolic Activation Modeling Nature Nonesterified Fatty Acids Obesity Obesity associated cancer Operative Surgical Procedures Ovarian hormone Ovariectomy Overweight Perimenopause Peripheral Physical activity Play Populations at Risk Postmenopause Premenopause Prevention strategy Process Production Publishing Rattus Recommendation Research Risk Rodent Model Role Sampling Signal Pathway Signal Transduction Site Testing Therapeutic Time Tissue Expansion Tissues Tumor Promotion Tumor Subtype Visceral Visceral fat Weight Gain Woman adipokines adiponectin cancer risk clinically relevant cytokine diet and exercise in vitro Assay in vivo individualized prevention innovation malignant breast neoplasm mammary mortality novel obesity risk pharmacologic pre-clinical precision medicine prevent risk minimization subcutaneous transplant model tumor tumor growth tumor microenvironment tumor progression tumorigenic

Abdomen Acceleration Adipose tissue Biological Body Composition Body Weight Body Weight decreased Body fat Breast Breast Cancer Risk Factor Chronic Clinical Data Coculture Techniques Data Deposition Development Distant Estrogens Fatty acid glycerol esters Future Goals Grant Growth Factor Growth and Development function Hip region structure Hormone Receptor Hormones In Vitro Incidence Infiltration Inflammation Inflammatory Insulin Resistance Intervention Knowledge Life Link Lipectomy Macrophage Macrophage Activation Malignant Neoplasms Mammary Neoplasms Measurable Mediating Menopause Metabolic Metabolic Activation Modeling Nature Nonesterified Fatty Acids Obesity Obesity associated cancer Operative Surgical Procedures Ovarian hormone Ovariectomy Overweight Perimenopause Peripheral Physical activity Play Populations at Risk Postmenopause Premenopause Prevention strategy Process Production Publishing Rattus Recommendation Research Risk Rodent Model Role Sampling Signal Pathway Signal Transduction Site Testing Therapeutic Time Tissue Expansion Tissues Tumor Promotion Tumor Subtype Visceral Visceral fat Weight Gain Woman adipokines adiponectin cancer risk clinically relevant cytokine diet and exercise in vitro Assay in vivo individualized prevention innovation malignant breast neoplasm mammary mortality novel obesity risk pharmacologic pre-clinical precision medicine prevent risk minimization subcutaneous transplant model tumor tumor growth tumor microenvironment tumor progression tumorigenic

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项目摘要

PROJECT SUMMARY/ABSTRACT The mechanisms that underlie the emergence of an obesity-associated increased risk in breast cancer after menopause are not fully understood. Increased adipose-derived estrogens certainly contribute to obesity-associated postmenopausal breast cancer, but additional mechanisms are also involved. Most women gain weight during menopause, and this is seen primarily as an increase in visceral adipose tissue (VAT) in the abdominal region. This in turn increases inflammation locally, systemically, and at distant sites such as subcutaneous adipose (SAT) in the breast, suggesting that changes in body composition during menopause could drive increased cancer risk. The long-term goal is to identify the mechanisms underlying obesity-associated tumor risk during menopause, and to use a precision- medicine approach to develop interventions to effectively minimize this risk in women with obesity. The overall objective of this grant is to determine the functional role that menopausal VAT deposition plays in obesity-related breast cancers. The central hypothesis is that increased VAT deposition during menopause mediates breast tumor development and growth through increased production of adipokines, cytokines, and growth factors that signal systemically to metabolically activate a subset of tumor-promoting macrophages in the mammary adipose/breast. Using a well-characterized preclinical rat model of obesity and postmenopausal breast cancer combined with a syngeneic orthotopic transplant model and in vitro assays, the central hypothesis will be tested with the following specific aims: 1) Determine the functional contribution of menopause-induced visceral adipose accumulation on mammary tumor development; 2) Interrogate how modifying insulin resistance, VAT, and adipose- derived signals alters macrophage activation, and the resulting impact on tumor development and growth after OVX. Preclinical findings will be confirmed in relevant clinical samples. The research proposed in this application is highly innovative as it will directly assess the biological role of visceral fat, inflammation, insulin resistance, and associated metabolic activation of macrophages in the tumor promotion process. Further, it will define a specific macrophage subtype that could be targeted to decrease obesity-associated cancers after menopause. This is significant as it will identify new targets for future pharmacological therapies and will provide the foundational platform for a precision medicine approach, using a clearly measurable target (decreased VAT), during a critical life stage (peri- menopause/ menopause), to decrease cancer risk in women with obesity.

项目摘要/摘要肥胖相关的乳腺癌风险增加的基础的机制更年期后未完全理解。脂肪衍生的雌激素的增加无疑有助于肥胖相关的绝经后乳腺癌，但还涉及其他机制。最多女性在绝经期间体重增加，这主要是内脏脂肪的增加腹部区域的组织（增值税）。反过来，这在本地，全身和在乳房中的皮下脂肪（SAT）等远处的部位，表明身体的变化更年期期间的组成可能会增加癌症的风险。长期目标是确定绝经期间与肥胖相关的肿瘤风险的机制，并使用精确医学方法开发干预措施以有效地最大程度地减少肥胖女性的这种风险。这这笔赠款的总体目标是确定更年期增值税扮演的功能作用在与肥胖相关的乳腺癌中。中心假设是在更年期通过增加的生产来介导乳腺肿瘤的发展和生长脂肪因子，细胞因子和生长因子有系统地发出代谢激活的子集乳腺脂肪/乳房中促肿瘤的巨噬细胞。使用良好的临床前肥胖和绝经后乳腺癌的大鼠模型与合成原位移植模型和体外测定法，中央假设将通过以下特定进行测试目的：1）确定更年期引起的内脏脂肪积累的功能贡献乳腺肿瘤发育； 2）询问如何改变胰岛素抵抗，增值税和脂肪派生的信号改变了巨噬细胞的激活，以及对肿瘤发展的影响 OVX后的生长。临床前发现将在相关的临床样本中得到确认。研究在此应用中提出的提议具有很高的创新性，因为它将直接评估内脏的生物学作用脂肪，炎症，胰岛素抵抗和巨噬细胞中巨噬细胞的代谢激活促进过程。此外，它将定义一个特定的巨噬细胞亚型更年期后减少与肥胖相关的癌症。这很重要，因为它将确定新目标用于未来的药理疗法，并将为精密医学提供基础平台在关键寿命阶段使用明显可测量的目标（降量降低）的方法（周期）更年期/更年期），以降低肥胖女性的癌症风险。