Key Takeaways

• In hormone-dependent cancers, the role of the microbiome in estrogen metabolism (the estrobolome) extends to an endocrine-microbiota axis based on reciprocal interactions with the endocrine system.
• Several mechanisms, including dysbiosis and chronic inflammation, may promote carcinogenesis.
• Modulation of the microbiome represents a promising — though still experimental — therapeutic approach.

A recent review proposes broadening the current understanding of the microbiota’s role in hormone-dependent cancers. Until now, this role has been viewed primarily through the concept of the estrobolome — that is, its involvement in estrogen metabolism. The authors now describe a true endocrine-microbiota axis based on reciprocal interactions between the microbiota and the endocrine system. This represents a major development, particularly for breast cancer, in which nearly 80% of tumors are hormone-sensitive.

From the Estrobolome to an Endocrine-Microbiota Axis

Hormone-dependent cancers, particularly hormone-sensitive breast cancer, are largely dependent on estrogen signaling, the regulation of which may be modulated by the gut microbiota.

The gut microbiota contains thousands of bacterial species. Among them, some produce beta-glucuronidases and sulfatases that reactivate estrogens eliminated by the liver, promoting their reabsorption. This group of bacteria constitutes the estrobolome. This concept has helped us understand how the microbiota could influence the body’s exposure to estrogens by promoting their intestinal recycling.

This view now appears incomplete. The authors demonstrate that interactions between the microbiota and the endocrine system extend beyond estrogen metabolism alone and propose the concept of an endocrine-microbiota axis, based on a bidirectional dialogue: The microbiota influences hormone metabolism, and hormones can also alter the composition and functions of microbial communities.

Multiple Mechanisms Involved in Carcinogenesis

Furthermore, the development and progression of hormone-dependent cancers may be influenced by several other mechanisms related to:

• An imbalance in the gut microbiota (dysbiosis). This promotes disruption of the intestinal barrier, allowing bacterial components to enter the circulation and leading to low-grade chronic inflammation, which creates an environment conducive to tumor proliferation.
• Certain metabolites produced by the microbiota. These may induce DNA alterations or epigenetic modifications that could promote tumor progression.
• The local microbiota present in breast and endometrial tissues. These could remodel the tumor microenvironment by locally modifying estrogen metabolism and activating inflammatory pathways.

Finally, the authors also emphasized that major hormonal life events — such as puberty, pregnancy, or menopause — are accompanied by changes in the microbiota that may influence, in the long term, estrogen exposure and, potentially, the risk for hormone-dependent cancers.

What Do the Data Show Regarding Breast Cancer?

A recent publication reports that several studies highlight differences in gut microbiota composition between women with breast cancer and healthy control individuals. These microbial profiles may contribute to variability in treatment response: Greater bacterial diversity is associated with a better response to immunotherapies, while low diversity appears to promote chemotherapy-related gastrointestinal toxicities.

Beyond the gut microbiota, the composition of the microbiota in the breast differs between tumor sites and adjacent healthy tissue, suggesting that certain microbial communities may play a role in local carcinogenesis.

The microbiota may also influence the response to hormone therapies. Translational studies suggest that certain gut bacteria alter the metabolism of tamoxifen as well as the concentrations of its main active metabolite, endoxifen, which may affect its efficacy. Conversely, aromatase inhibitors themselves may reshape the composition of the gut microbiota. These findings, which require confirmation in clinical trials, suggest that stratifying patients based on the functional signatures of their microbiota could improve the prediction of therapeutic response and toxicity.

Promising but Still Experimental Therapeutic Approaches

These findings pave the way for new therapeutic strategies aimed at modulating the microbiota. Their goal is either to reduce the activity of certain bacterial enzymes that promote estrogen reactivation or to stimulate the production of metabolites that may favorably modulate hormonal or immune pathways.

Several approaches are currently under investigation, including:

• Probiotics
• Prebiotics
• Selective inhibitors of bacterial enzymes involved in estrogen recycling
• Defined microbial consortia
• Fecal microbiota transplantation

However, the level of evidence is limited because these approaches are primarily supported by preclinical studies and a few early-stage human trials, with no evidence to date of a clinical benefit regarding the progression of hormone-dependent cancers. Longitudinal studies and large-scale intervention trials are therefore needed.

This story was translated from Univadis France, part of the Medscape Professional Network.