Genistein reduces the risk of local mammary cancer recurrence and ameliorates alterations in the gut microbiota in the offspring of obese dams

Authors: OLIVEIRA DE ANDRADE, FABIA - Georgetown University; LIU, FANG - Ocean University Of China; ZHANG, XIYUAN - National Institutes Of Health (NIH); MARIANA, ROSIM - Georgetown University; DANI, CAROLINA - Georgetown University; CRUZ, IDALIA - Georgetown University; Wang, Thomas - Tom; HELFERICHE, WILLIAM - Georgetown University; Li, Robert; HILAKIVI-CLARKE, LEENA - Georgetown University

Submitted to: Nutrients
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/5/2021
Publication Date: 1/11/2021
Citation: Oliveira De Andrade, F., Liu, F., Zhang, X., Mariana, R., Dani, C., Cruz, I., Wang, T.T., Helferiche, W., Li, R.W., Hilakivi-Clarke, L. 2021. Genistein reduces the risk of local mammary cancer recurrence and ameliorates alterations in the gut microbiota in the offspring of obese dams. Nutrients. 12(1):201. https://doi.org/10.3390/nu13010201.
DOI: https://doi.org/10.3390/nu13010201

Interpretive Summary: Flavonoids are bioactive compounds found in almost all fruits and vegetables. As a diverse group of phytonutrients, flavonoids, including isoflavones, possess antioxidant and anti- inflammatory properties. Certain flavonoids suppress methane production in the rumen and regulate short-chain fatty acid biosynthesis. In this study, we investigated the beneficial effect of genistein, a soybean derived phytoestrogen, on the structure and function of the gut microbiome in the offspring of obese dams and prevention of mammary cancer recurrence using animal models. Our results provided novel mechanistic insights into anti-inflammatory and anti-neoplastic activities of genistein; and these findings should be readily applicable for the management of gut health in small ruminants, particularly during parasitic infections.

Technical Abstract: Maternal obesity and high birth weight causes gut dysbiosis among offspring, and impairs anti-tumor immune responses and increases daughter's breast cancer risk and mortality. Because genistein intake 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 reduces their risk of local mammary cancer recurrence. We found that although starting genistein intake with tamoxifen therapy impaired offspring's response to this antiestrogen, genistein intake after tamoxifen therapy prevented the increased risk of local recurrence. Genistein supplementation reversed the elevated mRNA expression of multiple immunosuppressive genes, such as Tgfß1, Foxp3, Pd1, Ctla4 and Il-6 in the HFD offspring. Genistein also increased anti-tumor Cd8a expression. Further, when assessed at the end of tumor monitoring period, genistein increased the abundance of Akkermansia muciniphila, regardless of maternal diet. In the HFD offspring, genistein ameliorated gut microbial dysbiosis by reducing Gammaproteobacteria. High log abundance ratios between Lachnospiraceae and Christensenellaceae accurately predicted the status of local recurrence. Genistein enhanced microbial interactions between several genera in Lachnospiraceae and the genus AF12 in the family Rikenellaceae. Untargeted metabolome analysis indicated that maternal HFD altered the offspring's gut microenvironment to promote tumor Warburg effect. Only in the HFD offspring, genistein supplementation reduced genotoxic tyramine levels, and altered polyamine metabolism and resolving (aspirin) biosynthesis. If translatable to breast cancer patients, these findings suggest that dietary modification that improve the gut microbiota may prevent some breast cancer recurrences after tamoxifen therapy.