UC Irvine

Women with germline pathogenic variants in BRCA1 are predisposed to developing aggressive, early onset breast cancers, most commonly of the triple negative subtype. While defective DNA repair has long been considered the primary driver of BRCA1-associated tumorigenesis, accumulating evidence suggests that additional non-cell autonomous mechanisms contribute to disease initiation. In particular, BRCA1-mutant mammary glands exhibit pronounced epithelial hyperplasia and aberrant branching prior to tumor formation, raising the possibility that interactions between epithelial cells and the immune microenvironment play a causal role in early disease progression. In this dissertation, I investigate how immune cells specifically macrophages regulate premalignant remodeling in BRCA1-mutant mammary tissue. Using a genetically engineered mouse model of BRCA1 and p53 deficiency, I combine single-cell RNA-sequencing, spatial proteomic imaging, flow cytometry, and functional organoid assays to characterize immune dynamics across early stages of disease. I find that BRCA1-mutant mammary glands display an early expansion and spatial reorganization of distinct macrophage subsets, including CX3CR1 high inflammatory macrophages enriched for cytokine signaling pathways such as Oncostatin M. Spatial analyses reveal that these macrophage populations occupy defined niches relative to epithelial structures and hyperplastic lesions, suggesting specialized functional roles. Functional co-culture assays demonstrate that macrophages from BRCA1-mutant tissue are critical to drive exaggerated epithelial growth and branching in mammary organoids, implicating macrophage- derived signals as drivers of aberrant morphogenesis. Together, these findings support a model inwhich immune epithelial crosstalk contributes to early tumor promoting remodeling in genetically predisposed tissue. This work reframes BRCA1-associated breast cancer initiation as a process shaped not only by intrinsic epithelial defects, but also by immune regulation of tissue architecture. Understanding these early interactions may enable the development of immune based prevention strategies for individuals at high genetic risk.