Wednesday, July 30, 2025 7/30/2025

Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes

Award Number: R01CA266041
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/03/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes - PROJECT SUMMARY African American (AA) women are disproportionately affected by triple negative breast cancer (TNBC), a highly heterogeneous and aggressive subtype of breast cancer. We found that AA patients with TNBC have a higher risk of death from the disease than their European American (EA) counterparts, which is independent of their sociodemographic and clinical factors. Notably, this TNBC disparity is more obvious in patients receiving chemotherapy. However, the molecular mechanisms driving differential tumor response to chemotherapy and the consequent prognostic disparities in AA vs. EA TNBCs remains unknown. Most chemotherapy agents exert their cytotoxic effects through the induction of deadly DNA double-strand breaks (DSBs) that are repaired by two major mechanisms: error-free homologous recombination (HR) and error-prone non-homologous end- joining (NHEJ). Genomic stability and survival of tumor cells upon genotoxic treatments are known to depend on HR. Our pilot study showed that AA TNBCs tend to have higher expression of HR-related proteins and lower expression of NHEJ-related proteins compared with EA TNBCs. The AAA+ ATPase VCP has been suggested to influence the choice of DSB repair pathways in favor of HR as opposed to NHEJ. We recently reported that Ser784 phosphorylation of VCP is required for DNA damage repair and intra-tumor pSer784-VCP levels predict poor survival in TNBC patients, particularly those receiving chemotherapy. Our pilot data also showed that both total VCP protein and DNA damage-induced pSer784-VCP levels are higher in AA vs. EA TNBC samples. Based on these data, we hypothesize that AA TNBCs, relative to EA TNBCs, are intrinsically more capable of repairing chemotherapy-induced DSBs by HR as opposed to NHEJ due to differential expression levels and functionality of DSB repair factors including pSer784-VCP, which underlies their worse clinical outcomes. We propose three specific aims. First, we will confirm racial differences in protein expression of HR and NHEJ factors in tumor tissues obtained from two large cohorts of TNBC patients and examine their contribution to survival disparities. Second, we will experimentally compare HR and NHEJ efficiencies between AA and EA TNBC cell line and patient-derived mouse xenograft (PDX) models, and correlate the racial differences in DSB repair pathway choice and genotoxic chemotherapy effects. Third, we will examine the ability of pSer784-VCP to regulate DSB repair pathway choice and genotoxic chemotherapy effects in AA TNBC models. The proposed study will greatly improve our understanding of the molecular mechanisms underlying racial disparities in TNBC treatment response and outcomes. The results will also help create new disparity intervention strategies by establishing pSer784-VCP as a novel predictive biomarker and sensitizing target for genotoxic chemotherapy treatments in AA TNBCs. .


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 = $455,066 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	4	5/23/2025	NON-COMPETING CONTINUATION	$45,506
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	4	3/7/2025	NON-COMPETING CONTINUATION	$409,560
														Subtotal = $455,066

Issue Date FY: 2024 ( Subtotal = $468,984 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	000	3	2/8/2024	NON-COMPETING CONTINUATION	$444,300
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Cancer Cause and Prevention Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$24,684
														Subtotal = $468,984

Issue Date FY: 2023 ( Subtotal = $459,705 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	2	2/2/2023	NON-COMPETING CONTINUATION	$459,705
														Subtotal = $459,705

Issue Date FY: 2022 ( Subtotal = $513,768 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	001	1	3/28/2022	NEW	$3,194
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Cause and Prevention Research	000	1	2/3/2022	NEW	$510,574
														Subtotal = $513,768

Grand Total All Awards = $1,897,523

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Understanding the role of DNA damage repair in racial disparities of triple-negative breast cancer outcomes

Award Number: R01CA266041

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/03/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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