Genistein reduces the risk of local mammary cancer recurrence and ameliorates maternal high-fat diet induced alterations in gut microbiota in the offspring of obese dams

High birth weight increases daughter breast cancer risk and mortality, possibly by causing gut dysbiosis and suppressing anti-tumor immune responses. Because genistein modifies the gut microbiome and improves anti-tumor immunity, we investigated if feeding genistein to adult offspring of obesity inducing high fat diet (HFD) fed dams will increase offspring responsiveness to antiestrogen tamoxifen (TAM) and reduce the risk in local mammary cancer recurrence. Our results show that genistein or soy flour did not significantly affect the control offspring. At the end of the tumor monitoring period, genistein reversed the elevated levels of mRNA expression of multiple genes involved in tumor immune regulation in the HFD offspring. Genistein supplementation also increased the expression of anti-tumor CD8a expression. None of these differences were seen in tamoxifen resistant mammary tumors or recurring mammary tumors. Genistein ameliorated the maternal HFD induced gut microbial dysbiosis and increased the abundance of Akkermansia muciniphila in the offspring of rats regardless of maternal diets. Untargeted metabolome analysis suggested that maternal HFD altered the offspring gut microenvironment in a manner that may promote tumor Warburg effect. Genistein supplementation significantly increased gut phloretin levels and enhanced pathways related to the pro-resolving phase of inflammation and polyamine metabolism in the offspring of rats fed HFD. If translatable to breast cancer patients, these findings suggest that while genistein intake should not be initiated with TAM therapy, subsequent supplementation during the therapy might prevent recurrences after the therapy concludes, particularly in individuals with a high risk of recurrence.