Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment

Abstract

In breast cancer (BC) the employment of sequencing technologies for metagenomic analyses has allowed not only the description of the overall metagenomic landscape but also the specific microbial changes and their functional implications. Most of the available data suggest that BC is related to bacterial dysbiosis in both the gut microenvironment and breast tissue. It is hypothesized that changes in the composition and functions of several breast and gut bacterial taxa may contribute to BC development and progression through several pathways. One of the most prominent roles of gut microbiota is the regulation of steroid-hormone metabolism, such as estrogens, a component playing an important role as risk factor in BC development, especially in postmenopausal women. On the other hand, breast and gut resident microbiota are the link in the reciprocal interactions between cancer cells and their local environment, since microbiota are capable of modulating mucosal and systemic immune responses. Several in vivo and in vitro studies show remarkable evidence that diet, probiotics and prebiotics could exert important anticarcinogenic effects in BC. Moreover, gut microbiota have an important role in the metabolism of chemotherapeutic drugs and in the activity of immunogenic chemotherapies since they are a potential dominant mediator in the response to cancer therapy. Then, the microbiome impact in BC is multi-factorial, and the gut and breast tissue bacteria population could be important in regulating the local immune system, in tumor formation and progression and in therapy response and/or resistance.

Keywords: anticancer therapy; breast cancer; epigenetic modulation; estrobolome; immune responds; inflammation; microbiota; prebiotics; probiotics.

Figure 1

Chemotherapy treatments cause inflammation and mucositis in the intestinal epithelium of cancer patients. The cartoon representing a healthy epithelium (A) shows a wide diversity of symbiotic bacteria in the lumen and some inactive immune cells in the lamina propia. Both spaces are separated by a mucosal barrier. When patients are treated with chemotherapy (B), the mucosal barrier is damaged and pathogenic bacteria coexist with symbiotic bacteria in gut microbiota. Then, intestinal epithelial cells suffer DNA damage and tissue injury/cell apoptosis mediated by the increase of Reactive Oxygen Species (ROS) and cytokines signaling cascades. Cells affected by DNA damage release Damage-Associated Molecular Patterns (DAMPs), which together with Pathogen-Associated Molecular Patterns (PAMPs) released by pathogenic bacteria, are recognized by Toll-like receptors (TLRs). This signal is transmitted by the NFκB pathway, leading to the release of cytokines such as IL-1B, which enhance neutrophil/macrophage infiltration. ROS levels are increased in macrophages and neutrophils producing proinflammatory cytokines, tissue injury and apoptosis. On the other hand, B-lymphocytes produce IgA against the pathogenic bacteria. When the mucosal barrier is broken and the tissue injury advances (C), pathogenic bacteria interact with immune cells, increasing ROS production and provoking the activation of TNF- α as well as cytokines production, such as IL-12, also triggering inflammation.

Figure 2

Effect of probiotics and prebiotics on the gut microbiota and BC. Probiotics are living beneficial bacteria, which can restore a dysbiotic microbiota. Some species of Lactobacillus were described to have anticancer activities in BC among other positives effects. On the other hand, prebiotics are normally non-digestible fibers that enhance the proliferation of beneficial bacteria in the gut. Non-digestible fibers can be converted to phytoestrogens and SCFAs by some bacteria belonging to Bacteroidetes and Firmicutes phyla. These bacteria-derived metabolites, as well as other derivates, have tumor suppressor properties and anti-estrogenic and anti-proliferative effects that reduce BC risk.