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Mre11-Dependent DNA Damage Responses in Breast Cancer Pathogenesis

Award Number: R37CA227837
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mre11-Dependent DNA Damage Responses in Breast Cancer Pathogenesis - Project Summary Abstract The Mre11-Rad50-Nbs1 complex is a pleiotropic sensor of DNA double strand breaks that promotes ATM signaling, cell cycle checkpoint activation, and DNA repair. We have recently shown that Mre11 is an essential component of the tumor suppressive DNA damage response (DDR) in a murine model of breast cancer. Mre11 pathway deficiency has also been reported in a significant fraction of human triple negative (estrogen/progesterone receptor negative, HER2 non-amplified) breast cancers (TNBC), which are characterized by rampant chromosomal instability and nearly universal inactivation of the p53 pathway. In this project, we will investigate a role for Mre11-mediated tumor suppression in murine models of TNBC initiated by c-Myc overexpression, Rb1 deletion, and/or p53 deficiency. In Aim 1, we will analyze the effect of Mre11 deficiency on cell cycle checkpoint activation in response to oncogene-induced DNA damage. Time lapse microscopy of DNA damage and cell cycle state transitions will be performed in preneoplastic primary mammary epithelial cells. In Aim 2, we will use single cell whole genome sequencing to quantify stochastic chromosomal aberrations that accumulate during oncogene-induced replication stress in primary mammary epithelial cells. The effect of Mre11 and/or p53 deficiency on the chromosomal instability phenotype at different stages of tumorigenesis will be analyzed. In Aim 3, we will engineer Mre11 mutations in a Rb1/p53-deficient murine TNBC model to measure effects on tumor latency. Gene expression and genomic scar signatures associated with Mre11 deficient breast cancers will be determined, and compared to signatures of Brca1 deficiency. A panel of pharmacological DDR pathway inhibitors will be tested to identify targetable synthetic lethal vulnerabilities of Mre11 deficiency. Collectively, this project will provide insight into p53-independent mechanisms of Mre11-mediated tumor suppression, and identify molecular signatures and therapeutic susceptibilities of Mre11 deficient 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 = $422,092 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	003	7	5/29/2025	NON-COMPETING CONTINUATION	$42,208
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	002	7	11/15/2024	NON-COMPETING CONTINUATION	$379,884
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	6	11/13/2024	EXTENSION WITH OR WITHOUT FUNDS	$24
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	5	11/13/2024	NON-COMPETING CONTINUATION	-$24
														Subtotal = $422,092

Issue Date FY: 2024 ( Subtotal = $400,986 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	6	2/28/2024	EXTENSION WITH OR WITHOUT FUNDS	$379,884
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	002	6	6/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$21,102
2024	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	5	2/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $400,986

Issue Date FY: 2023 ( Subtotal = $413,651 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	5	3/15/2023	NON-COMPETING CONTINUATION	$33,768
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	5	12/1/2022	NON-COMPETING CONTINUATION	$379,883
														Subtotal = $413,651

Issue Date FY: 2022 ( Subtotal = $422,092 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	4	11/23/2021	NON-COMPETING CONTINUATION	$379,883
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	4	5/19/2022	NON-COMPETING CONTINUATION	$42,209
														Subtotal = $422,092

Issue Date FY: 2021 ( Subtotal = $409,161 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	3	1/28/2021	NON-COMPETING CONTINUATION	$20,459
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	3	11/4/2020	NON-COMPETING CONTINUATION	$388,702
														Subtotal = $409,161

Issue Date FY: 2020 ( Subtotal = $409,161 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	2	1/14/2020	NON-COMPETING CONTINUATION	$40,916
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	2	11/29/2019	NON-COMPETING CONTINUATION	$368,245
														Subtotal = $409,161

Issue Date FY: 2019 ( Subtotal = $409,161 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	1	11/29/2018	NEW	$409,161
														Subtotal = $409,161

Grand Total All Awards = $2,886,304

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Mre11-Dependent DNA Damage Responses in Breast Cancer Pathogenesis

Award Number: R37CA227837

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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