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

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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.