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

> **NIH NIH R03** · UNIVERSITY OF MASSACHUSETTS BOSTON · 2022 · $76,250

## Abstract

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 i...

## Key facts

- **NIH application ID:** 10438298
- **Project number:** 1R03CA270831-01
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS BOSTON
- **Principal Investigator:** Shailja Pathania
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,250
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438298

## Citation

> US National Institutes of Health, RePORTER application 10438298, A Novel BRCA1 Heterozygosity Driven Breast Cancer Mouse Model to Identify Tumor Initiating Events and Therapeutic Strategies (1R03CA270831-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10438298. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*