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A Novel BRCA1 Heterozygosity Driven Breast Cancer Mouse Model to Identify Tumor Initiating Events and Therapeutic Strategies

Award Number: R03CA270831
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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A Novel BRCA1 Heterozygosity Driven Breast Cancer Mouse Model to Identify Tumor Initiating Events and Therapeutic Strategies - PROJECT SUMMARY Women with BRCA1 (B1) mutation have an exceptionally high risk of developing breast cancer (70-80% by age 70y). B1 mutant cancer is triple negative which makes it refractory to hormone therapy. Platinum and PARP inhibitors (PARPi) have been effective against these tumors but the success of these drugs is marred by high incidence of resistance to these drugs over time. Furthermore, the only effective preventive strategy currently offered to these women is the life altering prophylactic mastectomy to remove the breast tissue. In light of limited treatment options available, it is critical that new therapeutic and preventive strategies be identified. Design of such strategies requires an understanding of early events in the breast cells that drive tumorigenesis. B1 heterozygous mouse models can help us identify these early changes in mammary epithelial cell populations as the cells become tumor cells. However, despite the well-established association between B1 heterozygosity and cancer predisposition in humans, there are currently no such B1 heterozygous mouse models that faithfully recapitulate this high risk of tumor formation upon B1 heterozygosity. B1 heterozygous mice are not tumor-prone. This makes it difficult to use these models to study the role of B1 heterozygosity and to identify early tumor promoting changes in the breast tissue. We have now established a B1 heterozygous mouse cancer model that is capable of addressing these questions. Our approach is based on our published work and preliminary data that reveals haploinsufficiency for replication stress suppression in B1 heterozygous cells. Our recent work has shown that B1 heterozygous mammary epithelial cells are especially defective/haploinsufficient in replication stress (RS) suppression. Given the importance of RS development in tumorigenesis, this effect would be a logical contributor to B1 mutant cancer development. We have found that B1 haploinsufficiency in RS suppression is enhanced by exposure to 4-nitroquinoline-1-oxide (4NQO1). In B1 heterozygous, but not B1 wild type tissue, RS serves as an efficient and abnormally rapid driver of tumor formation. Such an accelerated tumor model system could prove to be invaluable in understanding the earliest events in B1 mutant breast cancer. We have further used this mouse model to document early changes that occur in the breast tissue as different cell types (luminal and basal) respond to replication stress, and have identified new cell populations that emerge exclusively in B1 heterozygous mammary tissue. We plan to use this mouse model and human B1 mutant mammary organoids to ask two critical questions– i) what are the early events in the B1 heterozygous breast tissue that drives tumorigenesis (AIM1)? and ii) can PARPi be used as a preventive agent for women with B1 mutation (AIM2). PARPi has been used for maintenance therapy (continued use after initial response) and has shown potential in that context. However, it is not yet clear whether it can also be used as a preventive agent for women with BRCA1 mutation. We will address these questions in this grant application. This study will lay the foundation for extensive future studies that will identify novel therapeutic and preventive strategies for women with B1 mutation.


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 = $0 )
2025	2023	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	5/16/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $76,250 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	6/27/2023	NON-COMPETING CONTINUATION	$76,250
														Subtotal = $76,250

Issue Date FY: 2022 ( Subtotal = $76,250 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	100 MORRISSEY BLVD RM 80	BOSTON	MA	02125	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	3/8/2022	NEW	$76,250
														Subtotal = $76,250

Grand Total All Awards = $152,500

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A Novel BRCA1 Heterozygosity Driven Breast Cancer Mouse Model to Identify Tumor Initiating Events and Therapeutic Strategies

Award Number: R03CA270831

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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