Friday, March 21, 2025
3/21/2025
PROJECT SUMMARY While significant evidence has demonstrated that obesity increases the risk of metastasis, the molecular mechanisms by which obesity contributes to the metastatic progression of breast cancer are unclear. Furthermore, recent research in cancer development and progression has highlighted the role of hypoxia and dysregulated lipid metabolism. Research from our team and others demonstrate that lipid accumulation, which is associated with reduced patient outcomes, is greater in metastases compared to primary tumors. Furthermore, hypoxia, which is increased in obesity in the primary tumor, leads to sustained increase in the expression of specific genes after reoxygenation, a hypoxic memory. Our results demonstrate that hypoxic memory results in the expression of fatty acid synthase (FASN), which is the rate-limiting step in fatty acid synthesis, and pyruvate carboxylase (PC), which we have shown provides oxidative stress protection. In addition, the inflammatory cytokine interleukin-6 (IL-6), which is elevated in obesity, enhances the expression of CPT1A, the rate-limiting step in fatty acid oxidation (FAO) to supply energy. Our preliminary data show that the expression of these three proteins and their functional consequences of increased fatty acid synthesis and FAO are elevated in metastases compared to primary tumors. Thus, our preliminary results suggest that hypoxia may set the stage for dysfunctional lipid metabolism, where increased lipid synthesis and utilization occur concurrently with a balance towards lipid accumulation. However, the impact of dysfunctional lipid metabolism in obesity-driven metastasis is unknown despite the supporting evidence that hypoxia and IL-6 are enhanced in obesity. In the proposed studies, the research team will utilize multiple mouse models of obesity and metastatic breast cancer to evaluate the mechanistic basis by which hypoxic memory and IL-6 interact to stimulate obesity-driven breast cancer metastasis. They will test the hypothesis that obesity-associated increases in hypoxic memory and proinflammatory IL-6 signaling work in tandem to increase FA accumulation (FASN), FAO (CPT1), and cell survival (PC) to enhance metastases. These hypotheses will be tested through the completion of the following two aims: 1) determine the impact of hypoxic memory on lipid accumulation in obesity-driven metastasis, and 2) establish the interaction of hypoxic memory with chronic inflammation in obesity-driven metastasis. These studies will provide foundational evidence for developing targeted strategies to mitigate obesity-driven metastatic breast cancer.
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