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

摘要 乳腺癌是全世界妇女最常见的实体肿瘤之一。功能丧失突变 DNA修复基因BRCA1是增加BC发病率的临床上最相关的因素之一。尽管 与BC有如此强烈的联系，并不是每个携带BRCA1突变的女性都会患上BC。因此，身份识别 启动肿瘤发展的共同风险因素，如生活史事件，将使发展成为可能 用于早期检测、预防和可能的靶向治疗的生物标记物。多斯桑托斯实验室发现 尿路感染(UTI)引起的全身变化重塑乳腺转录组 上皮细胞(MECs)和组织微环境。因此，我们假设UTI是一种生命史。 促进卑诗省发病率的事件。具体地说，我假设UTI诱导MEC的改变并修改 在BRCA1基因敲除小鼠中，乳腺间质和免疫细胞中的肿瘤将发展得更快。我有过 用单细胞RNA测序评估乳腺组织的变化，并将进一步调查这些发现 通过采用多色流式细胞术、组织病理学、移植实验和 有机体研究。总体而言，本研究的意义在于：i)更好地理解 BRCA1-BC的肿瘤起始和早期进展，II)确定乳腺中免疫抑制细胞的变化 尿路感染产生的组织，以及iii)证明尿路感染是BRCA1患者的一种新的BC危险因素 突变。这些方法的结果将提供一个更深层次的机械理解如何具体 生活史事件调节微血管内皮细胞对促癌信号的反应。此外，这项提案 将提供对BRCA1的作用以及感染后产生的系统信号的影响的新的认识， 改善乳腺间质和免疫细胞功能。

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.