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: 10588256
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588256
• 关键词: 4-Nitroquinoline-1-oxide; Acceleration; 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; Early identification; 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; Poly(ADP-ribose) Polymerase Inhibitor; Population; Predisposition; Prevention; Prevention strategy; Preventive; Proliferating; Publishing; Refractory; Role; Stains; Therapeutic; Time; Tissues; Tumor Promotion; Water; Wild Type Mouse; Woman; Work; breast tumorigenesis; cancer predisposition; cell type; chemotherapeutic agent; design; effectiveness evaluation; efficacy testing; high risk; hormone receptor-negative; hormone therapy; 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; tumor initiation; 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.

项目摘要 BRCA1（B1）突变的女性患乳腺癌的风险异常高（到年龄为70-80％ 70y）。 B1突变癌为三重阴性，使其对马酮治疗难治性。铂和par 抑制剂（PARPI）对这些肿瘤有效，但这些药物的成功受到高的伤害 随着时间的推移，对这些药物的抗性发生率。此外，目前唯一有效的预防策略 提供给这些妇女的是改变预防性乳房切除术以去除乳房组织的生活。鉴于有限 可用的治疗方案，必须确定新的治疗和预防策略至关重要。设计的设计 这种策略需要了解驱动肿瘤发生的乳腺细胞中的早期事件。 B1 杂合小鼠模型可以帮助我们确定乳腺上皮细胞种群的这些早期变化 细胞成为肿瘤细胞。然而，尽管B1杂合性与 癌症在人类中的易感性，目前没有这样的B1杂合小鼠模型 在B1杂合性时概括了这种高肿瘤形成的风险。 B1杂合小鼠不容易肿瘤。 这使得很难使用这些模型研究B1杂合性的作用并鉴定早期肿瘤 促进乳房组织的变化。我们现在已经建立了一个B1杂合小鼠癌模型 能够解决这些问题。我们的方法基于我们已发表的工作和初步数据 这揭示了B1杂合细胞中复制应力抑制的单倍症。我们最近的工作有 表明B1杂合乳腺上皮细胞在复制中特别有缺陷/单倍弹性 压力（Rs）抑制。鉴于RS发育在肿瘤发生中的重要性，这种效果将是一种逻辑 B1突变癌发展的贡献者。我们发现RS抑制作用的B1单倍不足是 通过暴露于4-硝基喹啉-1-氧化物（4NQO1）来增强。在B1杂合子中，但不是B1野生型组织RS 是肿瘤形成的有效且绝对的快速驱动器。这样的加速肿瘤模型系统 在理解B1突变乳腺癌中最早的事件中，可能被证明是无价的。我们还有更多 使用该鼠标模型记录乳腺组织中发生的早期变化，作为不同的细胞类型（腔 和基本）应对复制应力，并确定了仅在B1中出现的新细胞群体 杂合乳腺组织。我们计划使用该鼠标模型和人类B1突变体乳腺类细节 问两个关键问题 - i）B1杂合乳腺组织中的早期事件是什么 肿瘤发生（AIM1）？ ii）可以将PARPI用作B1突变女性的预防剂（AIM2）。 PARPI已用于维护治疗（初始响应后继续使用），并显示了潜力 那个上下文。但是，目前尚不清楚它是否也可以用作具有 BRCA1突变。我们将在此赠款申请中解决这些问题。这项研究将为 将来的广泛研究将确定B1突变女性的新型热和预防策略。