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.
Bibliographical noteFunding Information:
Funding: This work was supported by R01-CA164384 and American Institute for Cancer Research grant to L. Hilakivi-Clarke, and P30-CA51008 to Lombardi Comprehensive Cancer Center, Georgetown University (funding for Shared Resources).
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- Antiestrogen resistance
- Breast cancer
- Gut microbiota
- Tamoxifen therapy
- Tumor immune genes
PubMed: MeSH publication types
- Journal Article