Genistein Reduces the Risk of Local Mammary Cancer Recurrence and Ameliorates Alterations in the Gut Microbiota in the Offspring of Obese Dams

Abstract

The risk of recurrence of estrogen receptor-positive breast cancer remains constant, even 20 years after diagnosis. Recurrence may be more likely in patients pre-programmed for it already in the womb, such as in the daughters born to obese mothers. Maternal obesity persistently alters offspring’s gut microbiota and impairs tumor immune responses. To investigate if the gut dysbiosis is linked to increased risk of mammary cancer recurrence in the offspring of obese rat dams, we fed adult offspring genistein which is known to have beneficial effects on the gut bacteria. However, the effects of genistein on breast cancer remain controversial. We found that genistein intake after tamoxifen response prevented the increased risk of local recurrence in the offspring of obese dams but had no effect on the control offspring. A significant increase in the abundance of inflammatory Prevotellaceae and Enterobacteriaceae, and a reduction in short-chain fatty acid producing Clostridiaceae was observed in the offspring of obese dams. Genistein supplementation reversed these changes as well as reversed increased gut metabolite N-acetylvaline levels which are linked to increased all-cause mortality. Genistein supplementation also reduced genotoxic tyramine levels, increased metabolites improving pro-resolving phase of inflammation, and reversed the elevated tumor mRNA expression of multiple immunosuppressive genes in the offspring of obese dams. If translatable to breast cancer patients, attempts to prevent breast cancer recurrences might need to focus on dietary modifications which beneficially modify the gut microbiota.

Genistein-Derived ROS-Responsive Nanoparticles Relieve Colitis by Regulating Mucosal Homeostasis

“…Furthermore, the nonmetric multidimensional scaling (NMDS) plot of unweighted UniFrac distance showed a clear difference in the phylogenetic structure of fecal bacteria between the DSS treatment group and the control group (Figure D). Notably, the similar fecal microbiota in the GEN-NP-treated mice could be due to the probiotic role of GEN, − which, as a polyphenol, can influence the gut microbiota composition . These results prove that GEN-NP treatment can restore the microbial community of mice with colitis.…”

Maternal obesity and resistance to breast cancer treatments among offspring: Link to gut dysbiosis

“…It is possible that the diversity is reduced in OID offspring that have not yet reached puberty, but later the diversity in these offspring is increased 63 . We found increased gut microbial diversity in 8‐month‐old rats born to dams fed OID during pregnancy 175 . In humans, increased bacterial diversity was seen in 6‐week‐old infants of obese mothers born vaginally but not via c‐section 188 .…”

“…In preclinical and human studies, maternal obesity reduces the abundance of anti‐inflammatory, SCFA‐producing Clostridiaceae in the offspring 170,171 . Maternal obesity also increases the genus of Prevotella among offspring in humans and non‐humans primates 172–174 and in rats 175 . Prevotella inhibits SCFAs 150,176 .…”

The Effects and Mechanisms of Flavonoids on Cancer Prevention and Therapy: Focus on Gut Microbiota

“…Genistein intake after tamoxifen therapy reduced the risk of local mammary cancer recurrence in rats fed with a high fat diet 187 . Mechanistically, genistein lowered the abundance of inflammatory Enterobacteriaceae and Prevotellaceae while enriched the population of anti-inflammatory, SCFA-producing Clostridiaceae .…”