Microbiome-metabolome signaling interactions reduce obesity-mediated breast cancer risk

/Abstract: Diet is a main determinant of gut microbial diversity. Our group demonstrated diet shifts breast microbiome populations. In a non-human primate (NHP) model, our group showed that consumption of a Western or Mediterranean diet modulated breast tissue microbiota and microbial-derived metabolite profiles. The shift in the bacterial-produced metabolome was specific to breast tissue and was not observed in circulating plasma samples, suggesting tissue-specific regulation of the metabolite levels. Re-analysis of data grouping subjects by body adiposity along with diet indicates obesity and diet work in tandem to shift the breast microbiome and microbial- derived metabolome. Specifically, we show that % body fat negative correlated with breast tissue hippurate levels in NHP. Hippurate is one of the most abundant microbial–host co-metabolites. Conventional housed mice display 17-fold higher plasma hippurate concentrations than germ-free mice, demonstrating the reliance on bacteria for this metabolite generation. Hippurate exerts its biological signaling through a G-protein coupled protein receptor 109A (GPR109A), and literature indicates that GPR109A activation modifies lipid metabolism and inflammation. Our preliminary data indicates that breast cancer patients with obesity display reduced hippurate concentrations in their non-cancerous breast tissue than lean women, validating our NHP data demonstrating adiposity-associated microbial metabolome perturbations. Moreover, we show exogenous administration of hippurate reduced tumor progression in a syngeneic 4T1.2ER+ and genetic MMTV-PyMT mammary tumorigenesis model. The purpose of this study is to investigate the impact of microbiota-derived metabolite hippurate-mediated GPR109A signaling to reduce obesity-mediated breast cancer risk. We hypothesize that obesity and consumption of a Western diet reduces hippurate bioavailability, decreasing GPR109A receptor activation to promote inflammation, lipid metabolism, and mammary tumorigenesis. Exogenous supplementation of hippurate in Western diet-fed animals will reduce breast cancer risk and improve therapeutic responsiveness to improve outcomes. The following aims address the hypothesis: Aim 1: Investigate whether obesity shifts the bacterial-associated metabolome in breast cancer patients; Aim 2: Determine the impact of microbial-derived metabolite GPR109A receptor signaling on obesity-mediated ER+ breast cancer risk; and Aim 3. Investigate whether GPR109A ligands promotes therapeutic efficacy in metastatic ER+ breast cancer. Successful completion of this proposal will determine the functional relevance of key microbial-processed metabolites to reduce obesity-mediated breast cancer risk. We will also identify potential microbiota-produced metabolites that could be exogenously administered to promote therapeutic efficacy to improve breast cancer outcomes. Project Number: 1R01CA301353-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Katherine Cook | Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES, WINSTON-SALEM, NC | Award Amount: $622,071 | Activity Code: R01 | Study Section: Cancer Prevention Study Section[CPSS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11297959