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Abstract

Breast cancer is the most common cancer among females, with hormone-receptor– positive tumors comprising most cases. Growing evidence links the gut microbiome to carcinogenesis, and the estrobolome—a subset of gut microbes involved in estrogen metabolism—has been proposed as a contributor to breast cancer risk. However, specific estrobolome targets and underlying mechanisms remain poorly defined, and few studies integrate microbial, metabolomic, and dietary data to explore these pathways. This thesis synthesized findings from three components: 1) a scoping review identified relevant estrobolome features from mechanistic and experimental evidence in the literature; 2) a case–control study of newly diagnosed postmenopausal breast cancer in Canada used whole- metagenome shotgun sequencing and plasma and stool metabolomics at baseline and 6-months to both compare baseline case–control differences and to evaluate within-person changes over time; and 3) a case–cohort study of incident breast cancer in France to examine diet and metabolite associations with breast cancer incidence. The scoping review showed that estrobolome targets remain incompletely annotated and evidence showing their association to breast cancer is inconsistent. In the case–control study, baseline comparisons revealed no clear differences in estrogens or directly related microbial functions between cases and controls. Instead, case–control differences appeared in the broader hormone environment—including estrogen precursors, downstream metabolites, and phytoestrogens—and beyond hormones, including Alistipes spp., conjugated bile acids, and microbial pathways related to vitamin K2 biosynthesis, TCA-linked energy metabolism, amino acid metabolism, and NAD salvage. Follow-up analyses indicated that many of these same features changed from baseline to six months. The French case–cohort study supported the relevance of glycine-conjugated bile acids and vitamin K pathways and suggested potential diet– metabolite interactions that may contribute to breast cancer risk. Overall, this work expands the understanding of breast cancer–associated microbiome and metabolic pathways. Several microbial pathways warrant further mechanistic study and validation, including phytoestrogen metabolism, glycine-conjugated bile acid metabolism, vitamin K2 biosynthesis, TCA-related energy metabolism, amino acid metabolism, and NAD salvage pathways. These findings lay the groundwork for future multi-omics research to clarify microbiome-mediated pathways and evaluate their potential as targets for breast cancer prevention or treatment.