Grant Number:	1R37CA315609-01 Interpret this number
Primary Investigator:	Wang, Tengteng
Organization:	Rutgers Biomedical And Health Sciences
Project Title:	The Human Gut Microbiome and Incident Breast Cancer: a Prospective Epidemiologic Approach
Fiscal Year:	2026

PROJECT SUMMARY/ABSTRACT The etiology of postmenopausal breast cancer is complex, as reflected by the influence of hormonal and other non-hormonal factors across the life course. Emerging evidence suggests the gut microbiota and microbial metabolites may contribute to risk by regulating estrogen metabolism, systemic immunity, and inflammation. However, existing human studies are all retrospective and have not applied the whole-metagenome sequencing approach to provide species-level resolution. No prospective epidemiologic studies have characterized the gut microbiome before breast cancer diagnosis, nor systematically examined the stool microbiome and stool metabolome in breast cancer etiology using a multi-omics approach, leaving a critical gap in understanding whether microbiome alterations are a cause or consequence of disease. Leveraging the Nurses’ Health Study II, which includes over 18,000 women with pre-diagnostic stool samples, repeated assessments of diet and lifestyle, and paired blood samples in a subset, we propose the first large-scale prospective study integrating stool metagenomics, stool metabolomics, and circulating sex hormone and inflammation biomarkers to evaluate gut microbiome contributions to breast cancer risk. Our central hypothesis is that specific gut microbial features, including taxonomic composition, functional pathways, and stool microbial metabolites, are associated with breast cancer risk via hormone-related and non-hormonal mechanisms, and that these microbial features are shaped by host exposures across the life course. In Aim 1, we will identify associations of pre-diagnostic microbial taxonomic, functional pathways, and metabolomic features in relation to subsequent breast cancer risk in a nested case-control study with 500 incident breast cancer cases and 500 controls, overall and by estrogen receptor status. In Aim 2, we will examine associations between the fecal microbiome and plasma hormone and inflammation proteomics biomarker levels, and derive estrobolome-, testerobolome-, and inflammation-related microbial signatures, and elucidate how these signatures may be associated with breast cancer risk. In Aim 3, we will evaluate how breast cancer risk factors (e.g., reproductive history, adiposity, physical activity, night shift work) and key dietary exposures (e.g., alcohol, fruit/vegetable intake, coffee consumption) influence microbial signatures in 8,000 participants with existing shotgun metagenomics data, with attention to timing and duration of exposures. This innovative proposal brings together an interdisciplinary team of experts, along with the rich resources of a well-established cancer epidemiology cohort, to thoroughly investigate the role of the gut microbiome in breast cancer. By clarifying microbial pathways, linking them to hormonal and immune mechanisms, and identifying modifiable determinants, our work will address critical gaps in breast cancer etiology. Findings from this first large-scale prospective epidemiological study in the US on gut microbiome and breast cancer incidence may guide microbiome-targeted prevention strategies and inform interventions to reduce breast cancer risk.





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