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.
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.
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.
Alizadehmohajer, Negin et al. “Association between the microbiota and women’s cancers – Cause or consequences?.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 127 (2020): 110203. doi:10.1016/j.biopha.2020.110203
Aragón, Félix et al. “Inhibition of Growth and Metastasis of Breast Cancer in Mice by Milk Fermented With Lactobacillus casei CRL 431.” Journal of immunotherapy (Hagerstown, Md. : 1997) vol. 38,5 (2015): 185-96. doi:10.1097/CJI.0000000000000079
Bodai, Balazs I, and Therese E Nakata. “Breast Cancer: Lifestyle, the Human Gut Microbiota/Microbiome, and Survivorship.” The Permanente journal vol. 24 (2020): 19.129. doi:10.7812/TPP/19.129
Bodai, Balazs I, and Therese E Nakata. “Breast Cancer: Lifestyle, the Human Gut Microbiota/Microbiome, and Survivorship.” The Permanente journal vol. 24 (2020): 19.129. doi:10.7812/TPP/19.129
Chen, Sumei et al. “Dietary fibre intake and risk of breast cancer: A systematic review and meta-analysis of epidemiological studies.” Oncotarget vol. 7,49 (2016): 80980-80989. doi:10.18632/oncotarget.13140
Choudhry, Hani. “The Microbiome and Its Implications in Cancer Immunotherapy.” Molecules (Basel, Switzerland) vol. 26,1 206. 3 Jan. 2021, doi:10.3390/molecules26010206
Esposito, Maria Valeria et al. “Microbiome composition indicate dysbiosis and lower richness in tumor breast tissues compared to healthy adjacent paired tissue, within the same women.” BMC cancer vol. 22,1 30. 3 Jan. 2022, doi:10.1186/s12885-021-09074-y
Fernández, Leónides et al. “The Microbiota of the Human Mammary Ecosystem.” Frontiers in cellular and infection microbiology vol. 10 586667. 20 Nov. 2020, doi:10.3389/fcimb.2020.586667
Fink, Brian N et al. “Dietary flavonoid intake and breast cancer survival among women on Long Island.” Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology vol. 16,11 (2007): 2285-92. doi:10.1158/1055-9965.EPI-07-0245
García-Lafuente, Ana et al. “Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease.” Inflammation research : official journal of the European Histamine Research Society … [et al.] vol. 58,9 (2009): 537-52. doi:10.1007/s00011-009-0037-3
Gibson, Glenn R et al. “Expert consensus document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics.” Nature reviews. Gastroenterology & hepatology vol. 14,8 (2017): 491-502. doi:10.1038/nrgastro.2017.75
Goedert, James J et al. “Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study.” Journal of the National Cancer Institute vol. 107,8 djv147. 1 Jun. 2015, doi:10.1093/jnci/djv147
He, Yujing et al. “The relationship between dairy products intake and breast cancer incidence: a meta-analysis of observational studies.” BMC cancer vol. 21,1 1109. 15 Oct. 2021, doi:10.1186/s12885-021-08854-w
Hieken, Tina J et al. “The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease.” Scientific reports vol. 6 30751. 3 Aug. 2016, doi:10.1038/srep30751
Komorowski, A S, and R C Pezo. “Untapped “-omics”: the microbial metagenome, estrobolome, and their influence on the development of breast cancer and response to treatment.” Breast cancer research and treatment vol. 179,2 (2020): 287-300. doi:10.1007/s10549-019-05472-w
Kovács, Tünde et al. “Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors.” Scientific reports vol. 9,1 1300. 4 Feb. 2019, doi:10.1038/s41598-018-37664-7
Laborda-Illanes, Aurora et al. “Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment.” Cancers vol. 12,9 2465. 31 Aug. 2020, doi:10.3390/cancers12092465
Lakritz, Jessica R et al. “Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice.” International journal of cancer vol. 135,3 (2014): 529-40. doi:10.1002/ijc.28702
Li, Yan et al. “Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth.” Cell reports vol. 30,6 (2020): 1753-1766.e6. doi:10.1016/j.celrep.2020.01.035
Luu, Trang H et al. “Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells.” Cellular oncology (Dordrecht) vol. 41,1 (2018): 13-24. doi:10.1007/s13402-017-0353-5
Makarewicz, Małgorzata et al. “The Interactions between Polyphenols and Microorganisms, Especially Gut Microbiota.” Antioxidants (Basel, Switzerland) vol. 10,2 188. 28 Jan. 2021, doi:10.3390/antiox10020188
Mendoza, Luis. “Potential effect of probiotics in the treatment of breast cancer.” Oncology reviews vol. 13,2 422. 27 Sep. 2019, doi:10.4081/oncol.2019.422
Mikó, Edit et al. “Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness.” Biochimica et biophysica acta. Bioenergetics vol. 1859,9 (2018): 958-974. doi:10.1016/j.bbabio.2018.04.002
Mikó, Edit et al. “Microbiome-Microbial Metabolome-Cancer Cell Interactions in Breast Cancer-Familiar, but Unexplored.” Cells vol. 8,4 293. 29 Mar. 2019, doi:10.3390/cells8040293
Parida, Sheetal, and Dipali Sharma. “Microbial Alterations and Risk Factors of Breast Cancer: Connections and Mechanistic Insights.” Cells vol. 9,5 1091. 28 Apr. 2020, doi:10.3390/cells9051091
Pellegrini, Marianna et al. “Gut microbiota composition after diet and probiotics in overweight breast cancer survivors: a randomized open-label pilot intervention trial.” Nutrition (Burbank, Los Angeles County, Calif.) vol. 74 (2020): 110749. doi:10.1016/j.nut.2020.110749
Pugin, Benoit et al. “A wide diversity of bacteria from the human gut produces and degrades biogenic amines.” Microbial ecology in health and disease vol. 28,1 1353881. 1 Jan. 2017, doi:10.1080/16512235.2017.1353881
Ruo, Sheila W et al. “Role of Gut Microbiota Dysbiosis in Breast Cancer and Novel Approaches in Prevention, Diagnosis, and Treatment.” Cureus vol. 13,8 e17472. 26 Aug. 2021, doi:10.7759/cureus.17472
Salimi, Vahid et al. “Sodium butyrate promotes apoptosis in breast cancer cells through reactive oxygen species (ROS) formation and mitochondrial impairment.” Lipids in health and disease vol. 16,1 208. 2 Nov. 2017, doi:10.1186/s12944-017-0593-4
Sampsell, Kara et al. “The Gut Microbiota: A Potential Gateway to Improved Health Outcomes in Breast Cancer Treatment and Survivorship.” International journal of molecular sciences vol. 21,23 9239. 3 Dec. 2020, doi:10.3390/ijms21239239
Sharma, Manvi et al. “Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice.” PloS one vol. 15,12 e0234893. 31 Dec. 2020, doi:10.1371/journal.pone.0234893
Suzuki, Reiko et al. “Dietary fiber intake and risk of postmenopausal breast cancer defined by estrogen and progesterone receptor status–a prospective cohort study among Swedish women.” International journal of cancer vol. 122,2 (2008): 403-12. doi:10.1002/ijc.23060
Toi, Masakazu et al. “Probiotic Beverage with Soy Isoflavone Consumption for Breast Cancer Prevention: A Case-control Study.” Current nutrition and food science vol. 9,3 (2013): 194-200. doi:10.2174/15734013113099990001
Toumazi, Daniela et al. “An unexpected link: The role of mammary and gut microbiota on breast cancer development and management (Review).” Oncology reports vol. 45,5 (2021): 80. doi:10.3892/or.2021.8031
Urbaniak, Camilla et al. “The Microbiota of Breast Tissue and Its Association with Breast Cancer.” Applied and environmental microbiology vol. 82,16 5039-48. 29 Jul. 2016, doi:10.1128/AEM.01235-16
Yazdi, Mohammad Hossein et al. “Oral administration of Lactobacillus acidophilus induces IL-12 production in spleen cell culture of BALB/c mice bearing transplanted breast tumour.” The British journal of nutrition vol. 104,2 (2010): 227-32. doi:10.1017/S0007114510000516