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.

项目总结/文摘