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.

项目概要 携带 BRCA1 (B1) 突变的女性患乳腺癌的风险异常高（按年龄划分为 70-80%） 70 岁）。 B1 突变癌症是三阴性的，这使得它对激素治疗无效。铂金和 PARP 抑制剂（PARPi）对这些肿瘤有效，但这些药物的成功因高浓度而受到损害。 随着时间的推移，这些药物的耐药性发生率。此外，目前唯一有效的预防策略 为这些女性提供的是改变生活的预防性乳房切除术，以去除乳房组织。鉴于有限 尽管已有治疗方案可供选择，但确定新的治疗和预防策略至关重要。设计 这种策略需要了解乳腺细胞中驱动肿瘤发生的早期事件。 B1 杂合小鼠模型可以帮助我们识别乳腺上皮细胞群的这些早期变化： 细胞变成肿瘤细胞。然而，尽管 B1 杂合性和 人类的癌症易感性，目前还没有这样的 B1 杂合小鼠模型能够忠实地 概括了 B1 杂合性时肿瘤形成的高风险。 B1杂合子小鼠不易患肿瘤。 这使得使用这些模型来研究 B1 杂合性的作用和识别早期肿瘤变得困难 促进乳腺组织的变化。我们现在已经建立了 B1 杂合子小鼠癌症模型 有能力解答这些问题。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 杂合细胞中复制应激抑制的单倍体不足。我们最近的工作有 显示 B1 杂合乳腺上皮细胞在复制方面特别有缺陷/单倍体不足 压力（RS）抑制。鉴于 RS 发育在肿瘤发生中的重要性，这种效应是合乎逻辑的 B1 突变癌症发展的贡献者。我们发现RS抑制中B1单倍体不足 暴露于 4-硝基喹啉-1-氧化物 (4NQO1) 会增强。在 B1 杂合组织中，但不是 B1 野生型组织中，RS 作为肿瘤形成的有效且异常快速的驱动因素。这样的加速肿瘤模型系统 事实证明，这对于了解 B1 突变乳腺癌的最早事件具有无价的价值。我们还有进一步 使用该小鼠模型记录了乳腺组织中不同细胞类型（管腔）发生的早期变化 和基础）对复制压力做出反应，并确定了仅在 B1 中出现的新细胞群 杂合的乳腺组织。我们计划使用这个小鼠模型和人类 B1 突变乳腺类器官 提出两个关键问题 – i) B1 杂合乳腺组织中驱动的早期事件是什么 肿瘤发生（AIM1）？ ii) PARPi 能否用作 B1 突变 (AIM2) 女性的预防剂。 PARPi 已用于维持治疗（初始缓解后继续使用），并在以下方面显示出潜力： 那个背景。然而，目前尚不清楚它是否也可以用作女性患有糖尿病的预防剂。 BRCA1 突变。我们将在此拨款申请中解决这些问题。这项研究将为 未来的广泛研究将为患有 B1 突变的女性确定新的治疗和预防策略。