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

一种新型 BRCA1 杂合性驱动的乳腺癌小鼠模型，用于识别肿瘤起始事件和治疗策略

• 批准号: 10438298
• 负责人: Shailja Pathania
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438298
• 关键词: 4-Nitroquinoline-1-oxide; Address; Age; Applications Grants; Automobile Driving; BRCA1 Mutation; BRCA1 gene; Biological Models; Breast; Breast Cancer gene; Breast Cancer therapy; Breast Epithelial Cells; CHEK1 gene; Cancer Model; Cell model; Cells; Chemoresistance; Complement; Coupled; DNA Damage; DNA Sequence Alteration; Data; Death Rate; Development; Drug resistance; ERBB2 gene; Effectiveness; Esophageal Neoplasms; Estrogen receptor negative; Event; Exposure to; Face; Family; Female; Foundations; Future; Genes; Genetic Transcription; Goals; Hereditary Breast Carcinoma; Heterozygote; High-Risk Cancer; Human; Incidence; Life; Light; Longevity; Loss of Heterozygosity; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of esophagus; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary Tumorigenesis; Manuscripts; Modeling; Molecular; Mus; Mutation; Normal Cell; Operative Surgical Procedures; Organoids; Pathogenicity; Patient Agents; Pharmaceutical Preparations; Phosphorylation; Platinum; Population; Prevention; Prevention strategy; Preventive; Publishing; Refractory; Role; Stains; Therapeutic; Time; Tissues; Water; Wild Type Mouse; Woman; Work; base; breast tumorigenesis; cancer predisposition; cell type; chemotherapeutic agent; design; effectiveness evaluation; efficacy testing; high risk; hormone receptor-negative; hormone therapy; inhibitor; insight; lifetime risk; malignant breast neoplasm; mammary; mouse model; mutant; mutation carrier; neoplastic cell; novel; novel therapeutics; p53-binding protein 1; prophylactic mastectomy; replication stress; reproductive; response; success; transdifferentiation; tumor; tumorigenesis; young woman

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.

项目总结