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

项目摘要/摘要 乳腺癌中出现肥胖相关风险增加的机制 人们对绝经后的情况还没有完全了解。脂肪衍生的雌激素增加肯定会导致 肥胖与绝经后乳腺癌有关，但也涉及其他机制。多数 女性在更年期期间体重增加，这主要被认为是内脏脂肪的增加 腹部组织(增值税)。这反过来会增加局部、全身和全身的炎症。 乳房中较远的部位，如皮下脂肪(SAT)，表明身体的变化 更年期的成分可能会增加患癌症的风险。长期目标是确定 更年期肥胖相关肿瘤风险的潜在机制，并使用精确度- 采用医学方法制定干预措施，有效地将肥胖妇女的这种风险降至最低。这个 这笔赠款的总体目标是确定更年期增值税沉积所起的作用 与肥胖相关的乳腺癌。中心假设是增值税沉积在 绝经后通过增加促性腺激素分泌来调节乳腺肿瘤的发生和生长 脂肪因子、细胞因子和生长因子，系统地发出信号，通过代谢激活一组 乳腺脂肪/乳房中促进肿瘤的巨噬细胞。使用一种特征良好的临床前阶段 肥胖和绝经后乳腺癌合并同种异体原位移植的大鼠模型 移植模型和体外试验，中心假说将用以下特定的 目的：1)确定更年期引起的内脏脂肪积聚对 乳腺肿瘤的发展；2)询问如何改善胰岛素抵抗、增值税和脂肪- 衍生信号改变巨噬细胞的激活，从而影响肿瘤的发展和 OVX之后的增长。临床前发现将在相关临床样本中得到确认。这项研究 在这一应用中提出的建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 肿瘤中的脂肪、炎症、胰岛素抵抗和巨噬细胞的相关代谢激活 推广过程。此外，它还将定义一种特定的巨噬细胞亚型，该亚型可以作为靶向 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 为未来的药物治疗提供了基础平台，将为精准医学 在关键的生命阶段(围产期)使用明确可衡量的目标(降低增值税)的方法 更年期/更年期)，以降低肥胖女性的癌症风险。

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.