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

摘要 乳腺癌是世界范围内女性最常见的实体肿瘤之一。功能丧失突变 DNA修复基因BRCA 1是增加BC发病率的最临床相关因素之一。尽管 尽管与BC有如此紧密的联系，但并不是每个携带BRCA 1突变的女性都会患上BC。因此，识别 合作的危险因素，如生活史事件，启动肿瘤的发展将使发展 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癌的转录组， 上皮细胞（MEC）和组织微环境。因此，我们假设UTI是一种生活史， 促进BC发病率的事件。具体来说，我假设UTI诱导MEC的改变， 乳腺基质细胞和免疫细胞，使Brca 1基因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，这项拟议研究的意义在于：i）更好地了解 Brca 1-BC中的肿瘤起始和早期进展，ii）鉴定乳腺癌中的免疫抑制性细胞变化， UTI导致的组织，和iii）提供UTI作为BRCA患者中新的BC风险因素的理由1 突变。这些方法的结果将提供一个更深入的机械理解如何一个特定的 生活史事件调节MEC对促癌信号的反应性。此外，该提案 将提供一个新的认识Brca 1的作用，和感染后产生的系统信号的影响， 改善乳腺基质和免疫细胞功能。

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.