The intestinal microbiota is a large and diverse community of microorganisms designated to inhabit the human intestinal tract, consisting mainly of more than a thousand species of bacteria, but also fungi, viruses, archaea, and protozoa . The gut microbiome, also known as the “second genome” of the human body . is the sum total of the genetic information of the gut microbiota and is extremely complex in its functions. The gut microbiota prevents pathogenic microorganisms from attacking the body and is important in host metabolism, immunity and hormone regulation  . promoting health but also contributing to the development of disease under certain conditions.
Breast cancer is the third most common cancer worldwide; it is also the leading cause of death from cancer among women worldwide in 2018 . Breast cancer is a multifactorial disease, and proven risk factors include advanced age, early menarche, late menopause, age at first full-term delivery, low parity, infertility, hormone replacement therapy, family history of breast cancer, obesity, and type 2 diabetes, etc.; however, over 70% of women with breast cancer  do not carry any of these risk factors. Therefore, we consider that there are other risk factors for the development of breast cancer. Numerous studies in the past decade have shown how the gut microbiota influences the development of specific cancers in various organs, including breast cancer, through a series of complex mechanisms; human intestinal microbiota as a risk factor for breast cancer has received extensive attention in recent years, and more and more studies have reported the mechanism of interaction between gut microbiota and breast cancer, and research on the application of intestinal microbiota in the treatment of breast cancer has been increasing.
In this paper, we discuss the latest findings on the relationship between gut microbiota and breast cancer, including the association between the structural changes or disorders of intestinal flora and the development and prognosis of breast cancer, the mechanism by which gut microbiota acts on breast cancer through regulating immune response and influencing estrogen metabolism, and the association between gut microbial metabolites and breast cancer, in order to reveal the mechanism of breast cancer development in breast cancer patients and provide rationale and reference for the prevention and treatment of breast cancer.
2. Breast Cancer and Altered Structure of Intestinal Microbiota
Under normal conditions, the interactions between host and gut microbes will resist invasive pathogens and prevent tumorigenesis, whereas disruption of gut flora composition may put the body into a dysregulated state, and this alteration of the local microbial environment will lead to disease initiation and progression . As early as 1990, Mineli EB et al.  found significant differences in the gut flora of premenopausal breast cancer patients compared to healthy women by observing and counting the fecal extract after incubation under the microscope. Using a mouse model, Buchta Rosean C  et al. showed that the inflammation that occurs in the mammary gland may be associated with a disturbance in the gut flora, which will run through the whole process of tumor occurrence and progression and cross talk with tumor tissues.
Goedert JJ and co-workers published a series of studies that reduced beta-diversity and alpha-diversity of the gut microbiota in breast cancer patients after adjustment for age, body mass index (BMI), and other factors . A recent study in mice  also showed that the use of cephalosporins antibiotics (cephalexin) exacerbated the decrease in the community diversity of gut microbial and led to tumor formation, suggesting a causal relationship between antibiotic use and the incidence of breast cancer and further supporting the hypothesis of reduced intestinal bacterial diversity in breast cancer patients.
Contrary to these results, Chinese scholars Zhu J et al. found an increased diversity of gut microbiota in breast cancer patients compared with healthy controls, but there was little difference between premenopausal cases and controls, whereas postmenopausal women with breast cancer had higher species richness and species diversity than controls, and reported 14 potential microbial markers  that could be used to diagnose breast cancer in postmenopausal women.
It has also been suggested that gut flora may also be related to breast cancer stage. For example, the number of Blautia sp. in the feces of breast cancer patients increases with the increase in grades, and the total number of five bacteria including Bacteroidetes in stage II and III patients is higher . Recent studies have also found that HER2− breast cancer patients have a higher alpha diversity of microbiota and a more unique bacterial composition than HER2+ breast cancer patients . Fernandez MF  et al. also found that reduced numbers of Methylobacterium in breast cancer patients were associated with invasive-prone breast cancer.
These findings all suggest that gut microbiota can be used as a biomarker for the diagnosis and staging of breast cancer, but the exact role of the microbiota in the development and treatment of breast cancer still needs further study, and it remains unclear whether alterations in the microbiota cause the cancer or the cancer leads to alterations in the microbiota.
3. Gut Microbiota Function and Breast Cancer
There are various interactions between the human body and the intestinal microbiota. The host adjusts the composition of the microbiome in the body through its innate immune system in the intestine or its eating and living habits, but in turn, gut microbiota can also modulate the pathophysiological responses of the human body  . For example, the function of the metabolites of the intestinal flora is like the hormones produced by the human body. They are synthesized and released by the intestinal microbes, absorbed into the blood circulation, and then transferred to other anatomical locations, where they exert their biological effects.
3.1. Gut Microbiota Influences Estrogen Metabolism
Estrogen has been shown to promote breast cancer and many studies have elucidated its mechanisms, including the induction of mitochondrial gene expression changes  and the promotion of breast epithelial cell and cancer cell proliferation . Breast cancer risk is directly associated with higher endogenous estrogen levels and differences in estrogen metabolism, which is more significant in postmenopausal women  . The association between gut microbes and estrogen has been proposed since the last century . and Plottel CS and Blaser MJ defined all the genes involved in estrogen metabolism in gut bacteria in 2011 . called “estrobolome” genes. Goedert and collaborators demonstrated that intestinal microbial diversity was positively associated with systemic, non-ovarian estrogens in both men and postmenopausal women, but not in premenopausal women  .
The intestinal microbiota is a key determinant of estrogen metabolism, and the intestinal flora is a major player in estrogen metabolism. Bacteria can uncouple the bound estrogens in the bile excreted into the intestine, and the uncoupling (or unbound) products are more easily reabsorbed into the bloodstream and enter the hepatic circulation, resulting in high levels of estrogenic substances in the body  . While high estrogen levels have been mentioned above as a risk factor for breast cancer, the interaction of gut flora with estrogen in humans may be the pathway leading to the development and progression of breast cancer. Bacterial β-glucosidase is responsible for the uncoupling of estrogens, which is encoded by the GUS gene   and the BG gene . In recent years, studies have identified gastrointestinal microbial β-glucosidase profiles, which have been established so that we may be able to adjust the body’s estrogen metabolism by altering the intestinal microbiota and further regulate the progression of breast cancer.
3.2. Gut Microbiota and the Immune Response in Breast Cancer Patients
Increased risk of breast cancer is associated with the presence of chronic, persistent and dysregulated inflammation  . The intestinal mucosa has a huge surface area, colonized with a large number of microorganisms. These microbiotas interact with the host immune system and are involved in the development and functional regulation of the immune system, exerting an influence that cannot be ignored on the immune environment of the whole body, even the immune microenvironment    within the tumor. LAKRITZ JR and co-workers found that oral administration of L. reuteri reduced the risk of breast cancer in mice by stimulating the development of host CD4+CD 25+ T cells . leading to the conclusion that the intestinal flora can induce proliferation and differentiation of regulatory T cells. Peterson DA and collaborators demonstrated that  gut microbiota can induce IgA protein expression through further studies. Goedert JJ finds only IgA-coated microbiota influence the risk of breast cancer through immune-mediated pathways, while non-IgA-coated microbiota does not . Sun J and collaborators established a mouse model  in which the intestinal microflora was depleted by administration of broad-spectrum antibiotics, and the experimental results pointed out that intestinal microbiota regulates the immune environment by inducing the expression of antimicrobial peptides. In addition, dysbiosis of the intestinal flora will lead to a decrease in lymphocytes and an increase in neutrophils, both of which will be detrimental to the survival of breast cancer patients . In turn, neutrophils, which are involved in the immune response to gut flora, also have a significant impact on breast cancer .
At the same time, there have been many studies that have shown that intestinal microbiota has an impact on the efficacy of immunotherapy in breast cancer patients. Therefore, regulating the intestinal flora to reduce the adverse effects of immunotherapy and increase the therapeutic effect will also become a kind of new combination therapy with strong applicability. Such as bactericides sp., especially B.thetaiotomicron and B.fragilis, can enhance the therapeutic effect of immunosuppressive(anti-CTLA-4 antibodies) . On the other hand, some species of intestinal microbiota may upregulate the immune response by enhancing antigen presentation or increasing T-cell recruitment in the local tumor environment . Bifidobacterium and Acinetobacter mucinum have also been found to be associated with enhanced anti-PD-L1 therapeutic response  . At present, the effect of gut microbiota on immunotherapy response of breast cancer patients is still unclear, and a foreign clinical trial (NCT02696759) is investigating whether gut microbiota can fight advanced breast cancer through immune modulation. It is also worth further studying to utilize probiotics to overcome the drug resistance and increase the efficacy of immunotherapy in some breast cancer patients.
3.3. Gut Microbial Metabolites and Breast Cancer
There is a complex and frequent communication between tumor tissue cells that strongly influences all aspects of tumorigenesis. At the same time, tumor cells interact systemically with the tumor and the entire body, including the intestinal microbiota. It has been found that the intestinal microbiota, through its metabolites, regulates all processes that promote tumor progression, including inflammation, angiogenesis, metabolism, and epithelial mesenchymal transition (EMT), acts on the tumor microenvironment(TME), and influences communication between the tumor microenvironment and the tumor and the entire organism . Intestinal microorganisms produce a large number of metabolites, such as secondary metabolites, lipopolysaccharides, proteins, fermentation products, and breakdown metabolites, which can enter the circulation and interfere with the steady state of the intestine and areas away from the intestine, acting as signaling mediators to influence breast cancer progression .
3.3.1. Short Chain Fatty Acids
In breast cancer cells, short chain fatty acids (SCFAs) increase the expression of the adhesion protein E-cadherin by inhibiting the Hippo-yap pathway and inhibit mitogen-activated protein kinase (MAPK) signaling by binding free fatty acid receptor 3 (FFAR3), with the final result of reducing the invasive capacity of breast cancer cells and limiting metastasis formation by inducing EMT and regulating proliferative pathways . SCFAs also inhibit histone deacetylase . prevent the expression of DNA repair proteins and compromise the integrity of DNA . so it can be said that SCFAs are regulators of invasion and apoptosis in breast cancer cells. In addition, studies have shown that intestinal alkaline phosphatase together with SCFAs enhance the tight junctions of the colonic mucosa and reduce the leakage of harmful pathogens and their carcinogenic potential  . Among SCFAs, butyrate is mainly produced by firmicutes and acts as a protective agent for the colon epithelium, providing energy to the colon epithelial cells . while propionate may be metabolized by Bacteroidetes, but the role of propionate in breast cancer has been less studied so far.
Lipopolysaccharide (LPS) can promote EMT, possibly by upregulating transforming growth factor β-1 (TGFβ-1) and parental anti-epithelial homologues 2/3 . and by promoting the expression of NF-KB and Toll-like receptor 4 (TLR4) in bile duct epithelial cells . Lipopolysaccharide also activates vascular endothelial growth factor (VEGF) receptors and induces angiogenesis in tumor tissues . Studies in breast cancer patients have also found that LPS stimulation of breast cancer cell lines MCF-7 and MDA-MB-231 induced cancer cell metastasis through activation of TLR4.
3.3.3. Secondary Metabolites
As early as 2002, deoxycholic acid (DCA) levels were found to be relatively high in the plasma of breast cyst fluid in postmenopausal breast cancer patients . suggesting that DCA can be involved in the carcinogenesis of organs that reach through the bloodstream, and it has subsequently been shown that DCA enhances the transcription of enzymes in cancer-associated fibroblasts . On the contrary, the literature has shown that lithocholic acid (LCA) has an inhibitory function on breast cancer, especially by interacting with the bile acid receptor TGR5 .
3.3.4. Cadaverine and Putrescine
In addition, cadaverine (CAD) can be considered a tumor suppressor of breast cancer, which is derived from the decarboxylation of lysine by lysine decarboxylase. The biosynthesis of CAD is down-regulated in stage 1 breast cancer, which may be due to the reduction of gut microbiota that produces CAD in stage 1 patients, and higher levels of lysine decarboxylase have also been found in patients with higher survival rates. Cadaverine inhibits the EMT in breast cancer cells by activating trace amino acid receptors 8 and 9 (TAAR8/9) and regulating the expression of metalloproteinase 9 . In addition, cadaverine can inhibit cell motility chemotaxis and metastasis to coordinate the occurrence of breast cancer. Another enzyme, ornithine decarboxylase(ODC), is responsible for the production of putrescine, which is upregulated in many cancers, and ODC is upregulated in many cancers, including breast cancer, and is associated with breast cancer progression, metastasis, and expression of estrogen receptor α . suggesting that putrescine may be a contributing factor to breast cancer.
3.3.5. Catabolic Products
Epidemiological studies have shown that high levels of phytoestrogens in the blood are negatively associated with breast cancer risk, unlike human endogenous estrogens  . Intestinal bacteria can convert some plant lignans from flaxseed, sunflower seeds, beans, etc., into mammalian lignans such as enterolactone and enterodiol. Enterolactone may be a selective modulator of estrogen signaling and have protective effects against breast cancer  . It has been suggested that regular intake of lignin-rich foods may reduce the risk of premenopausal breast cancer and increase the survival rate of postmenopausal women with breast cancer, leading some researchers to suggest that enterolactone may be a drug that can inhibit the proliferation of breast cancer cells . However, a recent experimental study by Parida S et al. concluded that enterolactone is neither a drug for the treatment of breast cancer nor a risk factor for the development of breast cancer .
It can be seen that most of the metabolites of the intestinal microbiota are capable of activating different cellular receptors or have different positive or negative effects depending on the content and environment.
4. Gut Microbiota and the Treatment of Breast Cancer
4.1. Gut Microbiota and Chemotherapy
The absorption and bioavailability of most chemotherapeutic drugs require exposure to intestinal enzymes prior to their entry into the circulation, and the intestinal flora is the primary producers of these enzymes, which can alter the mechanism of action and toxicity of chemotherapeutic drugs  . The gut microbiota has been shown to metabolize more than 40 drugs and may contribute to the therapeutic efficacy of many more . Lehouritis P et al. tested the direct interaction of E.coli and Listeria welshimeri monocytogenes with 30 commonly used chemotherapeutic drugs in vitro and in vivo and found that one or two of the 10 drugs, whereas the efficacy of the six drugs was enhanced .
4.2. Gut Microbiota and Radiotherapy
Radiation therapy is another important treatment modality in the treatment of breast cancer. It has been shown that sterile and microbiota-controlled mice receiving radiotherapy are less susceptible to dsDNA fragmentation in peripheral blood leukocytes than conventional mice . and that sterile mice are less susceptible to the toxic effects of cancer radiotherapy . Thus, control of the microbiota by antibiotics can reduce the side effects of radiotherapy, improve patient compliance and improve patient outcomes.
4.3. Probiotic Therapy
The role of Lactobacillus in the treatment and prevention of breast cancer growth and metastasis has been confirmed by more and more experiments. Lakritz JR et al. showed that oral supplementation alone with purified L.reuteri was sufficient to inhibit early carcinogenesis and increase the sensitivity of breast cells to apoptosis in two groups of breast cancer mice fed a western diet and manipulated the development of genetic susceptibility . In addition, oral administration of Lactobacillus acidophilus was shown to have anticancer activity in mice with mammary tumors . Hassan Z et al. demonstrated that  Enterococcus faecalis and Staphylococcus hominis can significantly inhibit cell proliferation, induce apoptosis, and cell cycle arrest, and that they have no cytotoxic effect on normal cells, making them a good alternative drug for breast cancer treatment.
4.4. Dietary Therapy
Changing dietary patterns affects the microbiome and indirectly influences disease development. A case-control study in Japan showed that regular consumption of casein and soy isoflavones from puberty onwards reduced the incidence of breast cancer in Japanese women ; Newman TM et al. also indicated that the Mediterranean diet could prevent breast cancer . Xue M et al. confirmed through experiments  that fucoidan increases the diversity of intestinal flora and can promote the intestinal barrier function, and he suggested fucoidan as a preventive agent for breast cancer.
These studies of gut flora in the treatment of breast cancer provide further evidence of the impact of gut flora on breast cancer and lay the groundwork for further research.
Breaking through the previous understanding of breast cancer, the intestinal flora plays a positive or negative role but non-negligible role in the progression of breast cancer. Although the importance of the gut microbiome in the development of breast cancer has been recognized, the mechanisms are not yet fully understood. On the one hand, it is due to the large and complex functioning of the gut microbiome; On the other hand, more than 90% of intestinal microbiota cannot be cultured or identified in vitro  . The complex interactions between the gut microbiota are far beyond our understanding, and the pathophysiological effects of gut dysbiosis that we have identified so far are mostly the result of the combined action of microbial groups rather than of individual microorganisms. Fortunately, the development of high-throughput sequencing technology has brought new breakthroughs in intestinal microbiome research, allowing us to explore more systematically and deeply the structure and function of gut microbes in breast cancer patients.
At present, the practical application of these research results is not ideal. Many researches are limited to mouse models, and a large number of clinical trials are still needed to translate these research results into clinical prevention and treatment of breast cancer patients. It is undeniable that research on the correlation between breast cancer and intestinal microbiota will eventually bring gospel to breast cancer patients. 1) Developing new breast cancer biomarkers, which is conducive to the early diagnosis of patients; 2) Good diet and lifestyle stabilize the intestinal flora, prevent the occurrence of breast cancer and tumor progression, improve the effect of radiotherapy and chemotherapy and prevent the side effects brought by radiotherapy and chemotherapy, and even prevent the recurrence of breast cancer, and improve the quality of life of patients; 3) New antitumor drugs may be developed according to the mechanism of intestinal microbiota promoting the progression of breast cancer.
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