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.