In 2020, 2.3 million women worldwide were diagnosed with breast cancer. The most frequently identified female cancer, breast cancer has links to changes in the gut and mammary microbiota. The microbiota at these sites appear to influence breast cancer risk, response to treatment, and recurrence. Since the early 2000s, the role of the human gut/ mammary microbiota and potential relevance in breast cancer has become a major area of interest in the scientific and medical communities.
This article (Part 1) will focus on how the gut and mammary microbiota and related dysbiosis (disrupted microbiota) may impact breast cancer risk (tumor formation and progression).
Part 2 will look at recent findings that suggest implications in treatments including surgery, radiation, and systemic therapies.
When healthy, the gut microbiota is capable of numerous beneficial activities. But dysbiosis may disturb these favorable mechanisms of action, many of which are linked to the risk of cancer development and progression. The gut microbiota is linked to breast cancer in several ways.
Let’s take a look at some of the key mechanisms.
Metabolism of bile acids
Bile acids found in the breast tissue originally come from the gut. One such bile acid called lithocholic acid (LCA) produced by intestinal bacteria has been found to exert antitumor effects in rodents with a 10-20% decrease in breast cancer cell proliferation. In addition, levels of lithocholic acid levels were found to be low in the fecal DNA of women with early-stage breast cancer compared to controls.
Production of anti-cancer metabolites
Generated from the fermentation of indigestible carbohydrates by the intestinal microbiome, short-chain fatty acids such as butyrate can induce cancer cell apoptosis (cell death), inhibit tumor formation, and reduce inflammation. A reduction in the proportion of butyrate-producing bacteria may increase tumorigenesis and inflammation.
Estrogen metabolism in the gut
The risk of estrogen-driven breast cancer in postmenopausal women is associated with the concentration and duration of exposure to estrogens. Gut bacteria are capable of deconjugating estrogen metabolites and reintroducing them into the circulation by increasing their systemic levels, hence changes in the estrobolome (those bacteria that have the genetic capability to metabolize estrogen) may influence the risk of estrogen receptor-positive breast cancer in postmenopausal women.
Amino acid degradation
Certain amines such as cadaverine, synthesized by bacterial enzymes, have been shown to inhibit breast cancer cell growth. Cadaverine levels were found to be reduced in patients with early-stage breast cancer, possibly due to decreased microbial production. Various members of the genera Enterococcus, Enterobacter, Escherichia, and Proteus have the ability to produce cadaverine.
Dysbiosis results in shifts in the bacterial metabolites toward an inflammatory state, which favors breast carcinogenesis. In addition, increased barrier permeability or “leaky gut” allows translocation of bacteria to distant sites such as the breast and promotes inflammatory responses.
Gut microbes when dysbiotic can damage DNA by triggering genomic instability, causing mutations, and increasing oxidative stress.
In addition to these possible mechanisms, several studies have observed an association between dysbiosis of the gut microbiota and breast cancer. In one example, 48 postmenopausal women with newly diagnosed breast cancer had a fecal microbiota that was less diverse and compositionally different compared with 48 similar women without breast cancer. Though steps were taken to minimize the effect, the case-control design precluded exclusion of reverse causality—that cancer caused the microbiota distinction. Still, the gut microbiota may affect breast cancer risk and may do so through estrogen-independent pathways.
Although breast tissue was once thought to be sterile, recent studies have shown that it contains a varied bacterial population. Several studies have linked specific bacterial taxa in the mammary microbiome with the initiation and progression of different tumor types. Moreover, the intersections of dysbiosis with diet, obesity, estrogens, and immune modulation have been considered important promoters of breast cancer.
Relevant to this discussion, healthy breast tissue microbes differ from those of tissue taken from women with breast tumors.
- In one study, researchers found different bacterial communities in the breast tissue of women with breast cancer in comparison to women suffering from benign breast disease.
- And in a 2022 study, a comparison between paired healthy and tumor tissues in 34 women revealed differences in bacterial composition and richness. Proteobacteria and Actinobacteria showed differences between the two groups: healthy tissues showed an increase of Actinobacteria and a decrease of Proteobacteria; the opposite appeared in tumor tissues. In addition, there was an overall decrease in diversity in tumoral tissues compared to healthy ones.
- Another study showed that higher relative abundances of specific bacteria (in the Enterobacteriaceae and Staphylococcaceae families) which can cause DNA damage in vitro (outside a living organism i.e. test tube or culture dish) were detected in breast cancer patients. The patients also had a decrease in some lactic acid bacteria, known for their anti-carcinogenic properties. Moreover, pathogenic bacteria are linked to cancers by various means: damaging DNA, producing carcinogenic metabolites, encouraging new tumors, and interfering with tumor suppressors.
It is important to note that several factors, such as ethnicity, dietary habits, geographical origin, lactation status, medications before surgery, and the method of sample collection can affect the composition of microbial tissues. However, whether differences in microbiota are a cause or effect of breast cancer has not been clarified.
Numerous in vitro studies suggest that probiotics demonstrate anticancer activities on breast cancer cells. Anti-proliferative activity, apoptosis, cytotoxicity, and cell cycle arrest were observed with various probiotics.
In animal studies, the results have also been promising. Lactobacilli in particular have been tested in mice transplanted or injected with tumor cells. For example, oral administration of Lactobacillus acidophilus showed decreased tumor growth rates in mice bearing breast tumors. Also, the probiotic Limosilactobacillus reuteri suppressed early-stage cancer and contributed to an increase in susceptibility to apoptosis in breast cells in mice.
Thus various strains have resulted in breast cell tumor inhibition and other positive effects. Improvements in the immune response driven by the application of probiotics were often observed and are likely to play a role.
Scant research has been conducted in humans though several clinical trials have been recorded.
In a study with Japanese women, regular consumption of a strain of Lacticaseibacillus casei and soy isoflavone from adolescence was significantly associated with decreased breast cancer risk.
In a small study with overweight breast cancer survivors, probiotics together with the Mediterranean diet improved microbiota diversity and composition as well as metabolic parameters better than the diet alone.
Consumption of fermented foods may also contribute to a protective metabolic environment due to their probiotic contents. Milk fermented by a strain of Lacticaseibacillus casei inhibited tumor growth, with less metastasis in a breast cancer mice model. These benefits were associated with the modulation of the immune response.
In that vein, the effect of dairy products intake on breast cancer risk was recently investigated in a meta-analysis comprised of 36 articles with over one million participants. It was found that different dairy products have varying effects on different cancer subtypes and menopausal status:
- Total dairy products intake showed a protective effect, especially for estrogen receptor-positive and progesterone receptor-positive women.
- Fermented dairy products showed reduced risk in postmenopausal but not in premenopausal women; non-fermented dairy products had no significant effect on breast cancer.
- Low-fat but not high-fat dairy products (which trended towards harm) protected the premenopausal population.
Prebiotics are substrates that are selectively utilized by host microorganisms conferring a health benefit. Non-digestible dietary fibers are often prebiotic but not always. And prebiotics can be non-fiber substances too.
Possible Mechanisms of Prebiotics and Fiber
- May combine with harmful and carcinogenic substances in the gut, lessening or eliminating threats.
- May increase the growth of probiotics, potentially inhibiting the proliferation of pathogenic bacteria and production of carcinogens. Prebiotics have been found to increase the abundance of Lactobacillus and Bifidobacterium among others.
- May enhance the ability of the estrobolome to eliminate estrogen (depriving breast cancer cells of a major fuel source), a factor in nearly 70% of breast cancers. Dietary fiber may alter the gut microbiota and influence estradiol metabolism through specific enzyme activities, such as β-glucuronidase in postmenopausal breast cancer patients.
Prebiotics haven’t been tested in breast cancer but studies using the prebiotic inulin in mouse models with colon cancer reported inhibited growth of tumors. Akkermansia muciniphila was most significantly enriched in the inulin-fed mice that experienced inhibited colon-cancer growth.
Moreover, non-digestible fibers can be converted to phytoestrogens and short-chain fatty acids by some bacteria belonging to Bacteroidetes and Firmicutes phyla. These bacteria-derived metabolites, among others, have tumor suppressor properties and anti-estrogenic and anti-proliferative effects that may reduce breast cancer risk.
Phytoestrogens (found in various foods, especially soy) may exert their effects on breast cancer by inhibiting estrogen synthesis and metabolism, as well as, through their antiangiogenic, antimetastatic, and epigenetic effects.
One recent study showed a lower risk of breast cancer mortality in the highest versus the lowest quintile of dietary isoflavone (phytoestrogen) intake but only in postmenopausal women.
However, one review cited two studies that found no such benefit between soy or other phytoestrogen intake and breast cancer in women.
Short-Chain Fatty Acids
Short-chain fatty acids such as acetate, propionate, and butyrate are produced by bacterial fermentation of dietary fiber in the colon. The anti-cancer effect of butyrate has been demonstrated in breast cancer cell cultures.
Produced by plants, dietary polyphenols are biotransformed by the gut microbiota into more available forms. In two of many benefits, polyphenols can inhibit the proliferation of pathogenic bacteria and increase the growth of beneficial counterparts. One study in a mouse model of breast cancer showed an inhibiting effect on tumor volume and a significant increase in tumor latency when polyphenol-containing foods were administered.
Several mechanisms of action have been identified for the chemoprevention effect of polyphenols; these include estrogenic/antiestrogenic activity, antiproliferation, induction of cell cycle arrest or apoptosis, prevention of oxidation, induction of detoxification enzymes, regulation of the host immune system, anti-inflammatory activity, and changes in cellular signaling.
Additionally, the increased consumption of fiber and polyphenols, readily available from a whole-food, plant-based diet, contributes to an overall increase in breast cancer survival.
The complex relationships between the gut and mammary microbiota and breast cancer are far from understood. The evidence presented here supports further study of the unique microbial characteristics in breast cancer, understanding its carcinogenesis, pathogenicity, or symbiosis in the tumor microenvironment. Strategies to modulate and sustain changes in gut microbiota, via dietary, prebiotic and/or probiotic supplementation show potential in the management of breast cancer risk.
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