NRSA for Steven Lewis: Investigating the relationship between the systemic response to infection and tumor initiation and progression in Brca1 breast cancer

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.