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

项目总结/摘要 与肥胖相关的乳腺癌风险增加的机制 绝经后的症状还不完全清楚。增加脂肪来源的雌激素肯定有助于 肥胖相关的绝经后乳腺癌，但也涉及其他机制。最 女性在绝经期体重增加，这主要表现为内脏脂肪的增加， 组织（VAT）在腹部区域。这反过来又会增加局部、全身和全身的炎症， 远处的部位，如乳房中的皮下脂肪（SAT），表明身体的变化 绝经期间的化学成分可能会增加癌症风险。长期目标是确定 绝经期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，以有效地减少肥胖妇女的这种风险。的 这项资助的总体目标是确定绝经期VAT沉积所起的功能作用 与肥胖有关的乳腺癌核心假设是， 更年期通过增加乳腺癌的产生来介导乳腺癌的发展和生长。 脂肪因子、细胞因子和生长因子，它们系统性地发出信号以代谢激活一个亚群， 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大鼠模型联合同基因原位 移植模型和体外试验中，中心假设将用以下特定的 目的：1）确定绝经引起的内脏脂肪堆积对 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活化，以及由此产生的对肿瘤发展的影响， OVX后生长将在相关临床样本中确认临床前结果。研究 本申请中提出的方法是高度创新的，因为它将直接评估内脏的生物学作用。 脂肪、炎症、胰岛素抵抗和肿瘤中巨噬细胞的相关代谢活化 晋升过程。此外，它将定义一个特定的巨噬细胞亚型，可以靶向 减少绝经后与肥胖相关的癌症。这一点意义重大，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 在关键的生命阶段，采用明确可衡量的目标（减少增值税）的方法（2010年）， 绝经期/绝经期），以降低肥胖妇女的癌症风险。

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.