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Impact of hypoxia on lipid metabolism in obesity-driven breast cancer progression

Award Number: R01CA271597
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/28/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Impact of hypoxia on lipid metabolism in obesity-driven breast cancer progression - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $641,634 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	002	3	6/9/2025	NON-COMPETING CONTINUATION	$64,163
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	3	11/26/2024	NON-COMPETING CONTINUATION	$577,471
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	001	3	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $641,634

Issue Date FY: 2024 ( Subtotal = $609,551 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	001	2	4/15/2024	NON-COMPETING CONTINUATION	$32,080
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	2	11/3/2023	NON-COMPETING CONTINUATION	$577,471
														Subtotal = $609,551

Issue Date FY: 2023 ( Subtotal = $655,384 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Biology Research	000	1	12/28/2022	NEW	$655,384
														Subtotal = $655,384

Grand Total All Awards = $1,906,569

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Impact of hypoxia on lipid metabolism in obesity-driven breast cancer progression

Award Number: R01CA271597

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/28/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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