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Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk

Award Number: U01CA272424
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/12/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk - The objective of this proposal is to determine how high fat diet (HFD)-induced lipid dysregulation links obesity with increased breast cancer (BC) risk. Epidemiologic studies have confirmed that obesity increases the risk and mortality of BC, but the molecular mechanisms of obesity/breast cancer associations remain largely unknown. Our recent studies demonstrate that lipid chaperone A-FABP (adipose fatty acid binding protein, also known as FABP4) promotes obesity-associated BC by intracellular regulating pro-tumor activity in tumor associated macrophages (TAMs) and extracellular enhancing aggressive phenotype of BC cells. Thus, A- FABP might represent a new factor linking dysregulated lipid metabolism with obesity/BC risk. Moreover, we observed that obesity can be induced by consumption of different types of HFDs, including saturated fats (e.g. cocoa butter) or unsaturated fats (e.g. olive oil, fish oil). However, only cocoa butter HFD-induced obesity was associated with increased A-FABP expression and mammary tumor growth. These observations suggest a novel concept that not all HFD-induced obesity is tumorigenic. Given the undefined links underlying obesity- induced BC risk, we hypothesized that HFDs rich in saturated fats promote BC risk through A-FABP-mediated immune and metabolic regulations. As such, A-FABP offers a novel therapeutic target and biomarker for obesity-associated BC risk. Three complementary but independent specific aims are designed to address our central hypothesis. Aim 1 is to determine the molecular mechanisms by which different HFDs upregulate A- FABP for BC risk. We will identify which HFDs promote mammary tumor risk and further dissect how the “bad” fat drives intracellular A-FABP expression in TAMs and promotes extracellular A-FABP secretion from adipocytes. Aim 2 is to delineate the downstream metabolic mechanisms of HFD-upregulated A-FABP in BC risk and immunotherapy. We will delineate how intracellular A-FABP in TAMs regulates the FA oxidation (FAO)/HIF2α/PD-L1 pathway for immune suppressive function, followed by delineation of how extracellular A- FABP reprograms lipid metabolic profile in BC cells to enhance their aggressive phenotype. We will further evaluate if blocking A-FABP activity with our unique humanized antibodies improves A-FABP-induced metabolic dysregulation and reduces obesity/BC risk. Aim 3 is to evaluate A-FABP as a biomarker for obesity- associated BC in humans. We will determine the function of A-FABP in peripheral monocytes and measure the levels of soluble A-FABP in serum and A-FABP expression in tumor stroma using specimens collected from lean and obese women with or without BC. Successful completion of this proposal will determine the “bad HFDs” in promoting BC risk and identify the molecular and metabolic mechanisms by which A-FABP mediates the pro-tumorigenic activities in HFD-induced obesity/BC risk.


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 = $1,170,632 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	003	4	8/13/2025	NON-COMPETING CONTINUATION	$1,170,632
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	000	3	10/25/2024	NON-COMPETING CONTINUATION	$0
2025	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	002	3	7/21/2025	NON-COMPETING CONTINUATION	$0
2025	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	001	2	7/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,170,632

Issue Date FY: 2024 ( Subtotal = $1,267,600 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	002	3	8/16/2024	SUPPLEMENT FOR EXPANSION	$155,500
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	001	3	8/15/2024	NON-COMPETING CONTINUATION	$1,112,100
2024	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	000	2	3/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,267,600

Issue Date FY: 2023 ( Subtotal = $1,152,838 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$1,152,838
														Subtotal = $1,152,838

Issue Date FY: 2022 ( Subtotal = $1,178,523 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	000	1	8/12/2022	NEW	$1,178,523
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cancer Biology Research	001	1	9/9/2022	NEW	$0
														Subtotal = $1,178,523

Grand Total All Awards = $4,769,593

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Determine the molecular and metabolic mechanisms by which A-FABP links dysregulated lipid metabolism-induced obesity/breast cancer risk

Award Number: U01CA272424

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/12/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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