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？

• 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
• 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

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.

项目概要/摘要 肥胖相关乳腺癌风险增加的机制 绝经后的情况尚不完全了解。脂肪源性雌激素的增加肯定有助于 肥胖相关的绝经后乳腺癌，但还涉及其他机制。最多 女性在更年期体重增加，这主要表现为内脏脂肪的增加 腹部组织（VAT）。这反过来又会增加局部、全身的炎症 较远的部位，例如乳房中的皮下脂肪（SAT），表明身体的变化 更年期期间的成分可能会增加癌症风险。长期目标是确定 更年期期间肥胖相关肿瘤风险的潜在机制，并使用精确的 医学方法来制定干预措施，以有效降低肥胖女性的这种风险。这 这笔赠款的总体目标是确定绝经期增值税存款所发挥的功能作用 与肥胖相关的乳腺癌。核心假设是，增值税存入增加 更年期通过增加乳腺肿瘤的产生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通过系统性信号代谢激活一部分 乳腺脂肪/乳房中的促肿瘤巨噬细胞。使用充分表征的临床前 肥胖和绝经后乳腺癌联合同基因原位大鼠模型 移植模型和体外测定，中心假设将通过以下具体测试进行检验 目的： 1) 确定更年期引起的内脏脂肪积累对 乳腺肿瘤的发展； 2) 询问如何改变胰岛素抵抗、增值税和脂肪- 衍生的信号改变巨噬细胞的激活，从而对肿瘤的发展和产生影响 OVX后的生长。临床前研究结果将在相关临床样本中得到证实。研究 本申请中提出的方法具有高度创新性，因为它将直接评估内脏的生物学作用 脂肪、炎症、胰岛素抵抗以及肿瘤中巨噬细胞的相关代谢激活 推广过程。此外，它将定义一种特定的巨噬细胞亚型，可以针对 减少绝经后与肥胖相关的癌症。这很重要，因为它将确定新的目标 用于未来的药物治疗，并将为精准医学提供基础平台 方法，在生命的关键阶段（围产期）使用明确可衡量的目标（降低增值税） 更年期/更年期），以降低肥胖女性的癌症风险。