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.
