A New Paradigm in the Relationship between Melatonin and Breast Cancer: Gut Microbiota Identified as a Potential Regulatory Agent

SIMPLE SUMMARY: The relationship between melatonin and breast cancer has been widely described. On the other hand, in recent years, an imbalance in the composition of the intestinal bacterial population has been linked as another possible trigger for this disease. Given that changes in the gut microbiota have been observed to stimulate the kinurenine pathway, reducing circulating melatonin levels, in this review, we summarize the relationship between circadian disruption and breast cancer, as well as the connection with dysbiosis as possible causing this pathology due to a series of changes that lead to an increase in circulating estrogen levels. ABSTRACT: In this review we summarize a possible connection between gut microbiota, melatonin production, and breast cancer. An imbalance in gut bacterial population composition (dysbiosis), or changes in the production of melatonin (circadian disruption) alters estrogen levels. On the one hand, this may be due to the bacterial composition of estrobolome, since bacteria with β-glucuronidase activity favour estrogens in a deconjugated state, which may ultimately lead to pathologies, including breast cancer. On the other hand, it has been shown that these changes in intestinal microbiota stimulate the kynurenine pathway, moving tryptophan away from the melatonergic pathway, thereby reducing circulating melatonin levels. Due to the fact that melatonin has antiestrogenic properties, it affects active and inactive estrogen levels. These changes increase the risk of developing breast cancer. Additionally, melatonin stimulates the differentiation of preadipocytes into adipocytes, which have low estrogen levels due to the fact that adipocytes do not express aromatase. Consequently, melatonin also reduces the risk of breast cancer. However, more studies are needed to determine the relationship between microbiota, melatonin, and breast cancer, in addition to clinical trials to confirm the sensitizing effects of melatonin to chemotherapy and radiotherapy, and its ability to ameliorate or prevent the side effects of these therapies.