Investigating the relationship between the systemic response to infection and tumor initiation and progression in Brca1 breast cancer

研究 Brca1 乳腺癌感染的全身反应与肿瘤发生和进展之间的关系

• 批准号: 10677263
• 负责人: Steven Macauley Lewis
• 金额: $ 4万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677263
• 关键词: American; Antibody Formation; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; BRCA1 Mutation; BRCA1 gene; Biological Assay; Biological Markers; Biological Models; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Epithelial Cells; Cell Communication; Cell Separation; Cell physiology; Cell surface; Cells; Coculture Techniques; Color; Counseling; DNA Repair Gene; Development; Early treatment; Epigenetic Process; Epithelial Cells; Epithelium; Event; Exhibits; Extracellular Matrix; Family; Fibroblasts; Flow Cytometry; Foundations; Future; Genetic; Germ-Line Mutation; Gland; Goals; Histopathology; Immune; Immune system; Immunization; Incidence; Infection; Inflammation; Knock-out; Knockout Mice; Laboratory Finding; Life; Life Style; Link; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Mature B-Lymphocyte; Medical History; Molecular; Mus; Mutation; Organoids; Outcome; Ovum; Pathway interactions; Patients; Physicians; Play; Population; Pregnancy; Prevention; Prevention therapy; Research; Risk; Risk Assessment; Risk Factors; Role; Scientist; Signal Transduction; Solid Neoplasm; System; Testing; Tissues; Training; Transplantation; Tumor Expansion; Urinary tract infection; Woman; Work; biomarker development; cancer risk; cancer stem cell; career; clinically relevant; demographics; differential expression; disorder prevention; early detection biomarkers; experience; experimental study; gene environment interaction; improved; in vivo evaluation; life history; loss of function; loss of function mutation; malignant breast neoplasm; mammary; mammary epithelium; mutation carrier; novel; response; single-cell RNA sequencing; targeted treatment; transcriptome; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Abstract Breast cancer (BC) is one of the most common solid tumors in women world-wide. Loss-of-function mutations in the DNA repair gene, BRCA1, is among the most clinically relevant factors that increases BC incidence. Despite such a strong link with BC, not every woman with a BRCA1 mutation will develop BC. Therefore, identification of cooperating risk factors, such as life history events, that initiate tumor development will enable development of biomarkers for early detection, prevention and potentially targeted treatments. The dos Santos lab has found that whole body changes resulting from urinary tract infection (UTI) remodel the transcriptome of mammary epithelial cells (MECs) and the tissue microenvironment. Therefore, we hypothesize that UTI is a life history event that promotes BC incidence. Specifically, I hypothesize that UTI induces alterations to MECs and modifies mammary stromal and immune cells in such a way that tumors in Brca1 knockout mice will develop faster. I have evaluated changes to mammary tissue with single cell RNA-sequencing and will further investigate these findings through the proposed aims using multi-color flow cytometry, histopathology, transplantation experiments and organoid studies. Overall, the significance of this proposed research is to: i) better understand mechanisms of tumor initiation and early progression in Brca1-BC, ii) identify immune-suppressive cellular changes in mammary tissue resulting from UTI, and iii) provide justification for UTI as a novel BC risk factor in patients with BRCA1 mutations. The outcome of these approaches will provide a deeper mechanistic understanding of how a specific life history event modulates the responsiveness of MECs to cancer promoting signals. Additionally, this proposal will provide a novel appreciation of the role of Brca1, and the effects of systemic signals produced after infection, in modifying mammary stromal and immune cell function.

抽象的 乳腺癌（BC）是全世界女性最常见的实体瘤之一。功能丧失突变 DNA 修复基因 BRCA1 是与临床最相关的增加 BC 发病率的因素之一。尽管 与 BC 的联系如此紧密，并非每个携带 BRCA1 突变的女性都会患上 BC。因此，鉴定 启动肿瘤发展的合作风险因素（例如生活史事件）将促进发展 用于早期检测、预防和潜在靶向治疗的生物标志物。多斯桑托斯实验室发现 尿路感染（UTI）引起的全身变化重塑了乳腺的转录组 上皮细胞（MEC）和组织微环境。因此，我们假设尿路感染是一种生活史 促进 BC 发病率的事件。具体来说，我假设 UTI 会引起 MEC 的改变并改变 乳腺基质和免疫细胞的这种方式使 Brca1 敲除小鼠的肿瘤发展得更快。我有 通过单细胞 RNA 测序评估了乳腺组织的变化，并将进一步研究这些发现 通过使用多色流式细胞术、组织病理学、移植实验和 类器官研究。总的来说，这项研究的意义在于：i）更好地理解 Brca1-BC 中的肿瘤发生和早期进展，ii) 识别乳腺中的免疫抑制细胞变化 UTI 产生的组织，以及 iii) 为 UTI 作为 BRCA1 患者新的 BC 危险因素提供了理由 突变。这些方法的结果将提供对特定的机制如何产生更深入的机制理解。 生活史事件调节 MEC 对癌症促进信号的反应。另外，本提案 将为 Brca1 的作用以及感染后产生的系统信号的影响提供新的认识， 改变乳腺基质和免疫细胞功能。