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The microorganisms that live symbiotically in human beings are increasingly recognized as important players in health and disease. The largest collection of these microorganisms is found in the gastrointestinal tract. Microbial composition reflects both genetic and lifestyle variables of the host.
This microbiota is in a dynamic balance with the host, exerting local and distant effects. Microbial perturbation dysbiosis could contribute to the risk of developing health problems. Various bacterial genes capable of producing estrogen-metabolizing enzymes have been identified.
Accordingly, gut microbiota is capable of modulating estrogen serum levels. Conversely, estrogen-like compounds may promote the proliferation of certain species of bacteria.
Therefore, a crosstalk between microbiota and both endogenous hormones and estrogen-like compounds might synergize to provide protection from disease but also to increase the risk of developing hormone-related diseases.
Recent research suggests that the microbiota of women with breast cancer differs from that of healthy women, indicating that certain bacteria may be associated with cancer development and lfy different responses to therapy. In this review, we discuss recent knowledge about the microbiome and breast cancer, identifying specific characteristics of the human microbiome that may serve to develop novel approaches for risk assessment, prevention and treatment for this disease.
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The incidence of breast cancer BC worldwide has risen to unprecedented levels in recent decades, making it the major cancer of women in many parts of the world nowadays [ 1 ]. It is not only the most frequently diagnosed cancer excluding non-melanoma skin cancers among women worldwide, affecting one in eight women during their lifetime, but also one of the leading causes of cancer mortality in women, with more than 0.
InBC accounted for approximately 1. Cancer in general is a complex disease, where a multitude of genomic and physiological alterations occur incessantly in the tumor tissue, contributing to the complexity of disease treatment and management. For this reason, and regardless of efforts that have been achieved by extensive research, the precise etiology for BC is still unknown, but the combination of genetic, epigenetic, and environmental factors has been identified.
Nevertheless, those genetic-epigenetic determinants and well-established risk factors only could explain a limited amount of the global burden of this disease [ 6 ]. Therefore, it is crucial to understand how these sporadic breast cancers arise in order to develop preventative strategies against this devastating disease. BC risk is directly related to higher levels of endogenous estrogens and differences in estrogen metabolism, especially among postmenopausal women [ 89 ].
The decline associated with menopause in age-specific incidence rates, known as the Clemmesen hook, is widely observed among women around the world [ 1011 ]. Reproductive history, alcohol intake, obesity, and use of hormone therapy exert their effects, at least in part, by modifying the time and intensity of the exposure of the mammary gland to steroidal hormones [ 12 ].
This hormonal regulation manifests, both clinically and molecularly, as distinct subtypes: Bacterial communities within the host could be one additional environmental factor related to BC, which has been only recently considered in sporadic breast cancers of unknown etiology.
In the recent years, there has been a strong interest in fully characterizing the microbiota associated with different parts of the body under different health conditions, due to the fact that different published studies have shown that bacterial communities vary across body habitats, establishing complex interactions between bacteria and the host [ 1415 ].
These studies have been possible with the use of deep-sequencing technologies for example, pyrosequencing technique, which provides a qualitative survey of relative abundances of microbiota, and quantitative polymerase chain reaction qPCR which may determine quantitative differencesand also due to the findings from the Human Microbiome Project analyses, which has demonstrated that the diversity and abundance of the signature microbes in each habitat varied among healthy subjects, with strong niche specialization both within and among individuals [ 14 ].
The terms microbiota and microbiome are often used as synonyms, but express two different meanings: The improvement of DNA-RNA sequencing methods has made possible to group microbiota composition into clusters, known as Operational Taxonomic Units OTUsbased on genetic sequence similarities of specific taxonomic marker genes. Each OTU may belong to different phyla, but new methods that resolve amplicon sequence variants ASVs from Illumina-scale amplicon data without imposing the arbitrary dissimilarity thresholds that define molecular OTUs, have been recently developed [ 171819202122 ].
ASV methods infer the biological sequences in the sample prior to the introduction of amplification and sequencing errors and distinguish sequence variants differing by as little as one nucleotide [ 23 ]. The human microbiota is the term applied to the universe of microbes that live in different habitats of our body mostly the gut, skin, vagina and mouth, but also the nose, conjunctiva, pharynx and urethra, among others.
The microbiota of each organ is distinct, and there is an important and functionally relevant inter-individual variability of microbiomes, which makes them a potential determinant of disease including cancer development [ 14 ].
Human bacterial composition contributes and affects different diseases including metabolic disorders, inflammatory and autoimmune diseases, and allergy [ 24 ], and even diseases where microbiota involvement seems unlikely [ 2526 ]. The microbiota has been also implicated in cancer development progression and aggressiveness at a variety of body sites [ 2527 ] including stomach [ 28 ], colon [ 29 ], liver [ 30 ], lung [ 31 ], and skin [ 32 ].
This review discusses important questions such as the role of the human microbiota in BC development, its ability to modulate inflammation, immunity and metabolism, and the possibility that both intestinal and local microbes could affect cancer prevention and be a new target for therapeutic approaches, thus improving the prognosis and quality of life of breast cancer patients.
The human gastrointestinal tract is colonized by a complex and diverse community composed of trillions of individual microorganisms comprising heterogeneous species of bacteria, viruses, archaea, and fungi [ 24 ].
Breast Cancer and Its Relationship with the Microbiota
Their collective bacterial genome harbors approximately fold more genes than the human genome [ 14 ]. So far, the human gastrointestinal tract is the best investigated microbiota and is serving as a model for understanding host—microbiota interactions and disease. Main phyla of the gut microbiota are FirmicutesBacteriodetesActinobacteriaProteobacteriaFusobacteriaVerrucomicrobiaTenericutes and Lentisphaerae ; and main genera are BacteroidesClostridiumFaecalibacteriumEubacteriumRuminococcusPeptococcusPeptostreptococcusLactobacillusStreptococcusStreptomyces and Bifidobacterium [ 25 ].
The human gut microbiota is helpful in physiologic activities such as digestion, metabolism, and homeostasis, and plays important roles in human health.
For example, it is essential in digestion and absorption of indigestible carbohydrates for humans dietary fiberproduction of vitamins B and K, metabolism of endogenous and exogenous compounds, and immunity. It is also actively involved in innate and cell-mediated immunity, helps to maintain intestinal barrier function, and assists with an appropriate immune response against pathogenic microbes [ 2534 ]. The composition of the intestinal microbiota is determined by several internal and external factors, including age, race, diet, maternal colonization, and hygiene, as well as host genetics and environmental exposures to xenobiotics and antibiotics [ 3435 ].
Additionally, some individual factors such as stress, travelling, or pharmacological treatment or drugs, can also directly and rapidly produce changes [ 25 ]. This complexity represents a challenge to the goal of phenotyping all these populations in each individual and comparing them with others [ 25 ].
A symbiotic relationship referred to as normobiosis between host and microbiota is critical to maintaining a balance homeostasis in the gut. This symbiotic relationship confers benefits to the host in many key aspects of life.
Thus, Helicobacter pylori infection is known to promote gastric cancer and gastric mucosal-associated lymphoid tissue GALT lymphoma [ 37 ], although H. In contrast to gastric carcinogenesis, recent evidence suggests that human disease is attributable not only to single pathogens but also key global changes in the microbiota [ 25 ].
In fact, altered host—gut microbiota interactions, caused by dysbiosis, seem to play an important role in colorectal carcinogenesis [ 39 ]. In this context, decreasing overall diversity has been associated with colorectal cancer [ 40 ]. Nevertheless, in colon cancer, the overabundance of a single 180100 species Fusobacterium nucleatum has been correlated with disease and with increased likelihood of lymph node metastasis [ 41 ].
But the lfy Bacteroidetes fragilis exerts a protective effect against colitis by modulating inflammatory immune responses in the gut [ 42 ]. The gastrointestinal tract exerts both local and long-distance effects in other parts of the body. The liver does not contain a known microbiota and is a good example of a cancer that is promoted by dysbiotic microbiota through long-distance mechanisms. Moreover, intestinal bacteria may promote liver cancer through proinflammatory microorganism-associated molecular patterns MAMPs and bacterial metabolites, both of which reach the liver via the portal vein [ 3043 ].
BC associations with estrogen levels could reflect differences among individuals in their intestinal microbial communities [ 46 ], as shown 50 years ago by Adlercreutz and collaborators, who demonstrated one of the fundamental roles of the gut microbiota [ 47 ].
More recently, Fuhrman and co-workers demonstrated that postmenopausal estrogen metabolism is associated with microbial diversity [ 13 ].
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The link between intestinal microbiota dysbiosis and breast cancer has been investigated in several case-control studies, and many hypotheses have been suggested, some of which underline the possible decrease in the metabolic ability of the microbiota and a weakness of the immune system [ 48 ]. The results of clinical studies on the relationship between gut microbiota and breast cancer are summarized in Table 1.
The studies targeting at the relationship between BC and gut microbiota are quite limited so far. Indeed, clinical studies have identified associations between the gut microbiota, and urinary estrogens and estrogen metabolites [ 13 ].
These metabolites are produced through estrogen metabolism by several bacteria included in Clostridia and Ruminococcaceae families [ 25 ]. In addition, others estrogen-like metabolites can be also produced by oxidative and reductive reactions in the gut and by an induced synthesis of estrogen-inducible growth factors, which might have a carcinogenic potential.
Other studies have focused on the relationship between gut microbiome and BC risk through estrogen-independent pathways [ 495253 ].
An enteromammary pathway by which some bacteria from the gut could reach the mammary gland via an endogenous route has been the most studied pathway [ 54 ]. A case-control study comparing the fecal microbiota between BC patients and paired controls found significantly altered microbiota composition and less diverse gut bacteria among the postmenopausal BC patients [ 52 ]. The gut microbiome of case patients had higher levels of ClostridiaceaeFaecalibacteriumand Ruminococcaceae ; and lower levels of Dorea and Lachnospiraceae.
A possible explanation may involve other known breast cancer risk factors such as adiposity and obesity, since in these circumstances the gut microbiota is less diversified [ 55 ]. The gut microbiota has been also related to the development of adiposity and obesity [ 55 ], and it is known that overweight and obese women have a higher risk of BC compared to healthy weight women, especially during the postmenopausal period [ 56 ].
Within the gut, Firmicutes and Bacteroidetes are the two main phyla involved in the colonic metabolism of indigestible nutrients, including dietary fibers and polyphenols [ 57 ]. Significant differences in the absolute numbers of total bacteria and of three bacterial groups FirmicutesFaecalibacterium prausnitziiand Blautia were observed in feces as a function of the body mass index BMI of women with early-stage breast cancer, with lower number of 118010 in overweight and obese patients [ 48 ].
The relation between these main phyla and BMI remains unclear [ 48 ]. Goedert and co-workers [ 53 ] investigated the role of immunity and inflammation in BC risk, and whether the gut microbiota differed in the composition of immune-recognized microbiota in a case-control study. Distributions of estrogen metabolites versus parent estrogen potentially reflecting differences in estrogen metabolism were essentially identical in cases and controls.
Levels of parent estrogens estrone and estradiol and major estrogen metabolites were all non-significantly higher in cases compared with controls [ 53 ]. Bard and colleagues [ 62 ] also evaluated the composition of the gut microbiota among BC patients with different clinical characteristics. The majority lley the participants were early-stage invasive ductal carcinoma. In addition, absolute numbers of Bifidobacterium and Blautiaand proportions of Faecalibacterium Prausnitzii and Blautiavaried according to clinical stages, suggesting that gut microbiota may be related with the development and evolution of BC.
In this study, significant differences were also observed pey absolute numbers of total bacteria and for some studied bacterial groups F.
Firmicutes and 18100 phyla were also the most numerous bacteria observed in the feces of 31 women with early-stage breast cancer [ 48 ].
This study evaluated the relationship between the composition of gut microbiota with the clinic-biological characteristics of BC, describing that the total number of BacteroidetesClostridium coccoides cluster, C. Moreover, authors found a significant decline in the abundance of total bacteria and in three bacterial groups Firmicutes 180100, Faecalibacterium prausnitziiand Blautia as a function of the Lry of participants, with lower number of bacteria in lsy and obese patients [ 48 ].
Some authors have also raised the question of the role of the mammary microbiome in modulating the risk of breast cancer development. It is also still unclear whether there is a specific microbial signature either for the presence of pathogenic strains or the absence of beneficial ones responsible of breast carcinogenesis. The results of clinical studies on the relationship between mammary microbiota and BC are also included in Table 1.
In this regard, it has been proposed that this breast microbiome contributes to lwy of healthy breast tissue by stimulating, for example, resident immune cells, although the type of bacteria and their metabolic activity, such as the ability to degrade carcinogens, may also contribute [ 44 ]. Only few studies have characterized which bacteria are present in breast tumor tissue and normal adjacent 1010 of women, finding mixed results in the breast tissue microbiota of patients with and without cancer.
These investigations are still in their infancy, and the evidence remains unclear on whether a difference exists between tumor and adjacent histologically-normal tissue from cancer patients. Thus, some studies by Urbaniak et al. Nevertheless, 81010 authors found a higher abundance of Escherichia coliknown for its cancer-promoting activity, in women with cancer compared with healthy controls.
The number of OTUs detected did not vary between paired normal and tumor tissue, indicating no significant difference in richness [ 44 ].
However, breast tumor tissue had significantly reduced amounts of bacteria: Of those 11 OTUs, 8 were more abundant in paired normal tissue and 3 were more abundant 1800 tumor tissue. Sphingomonas yanoikuyae lsy not present in the corresponding tumor tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis may be associated with BC.
Most of the works dealing with the microbiome of breast tissue describes a community characterized by a predominance of the phyla Proteobacteria and Firmicutes [ 446367 ], with the exception of one study that found a predominance of Bacteroidetes and very little Proteobacteria [ 66 ].
A diverse population of bacteria was detected within tissue collected from sites all around the breast. Proteobacteria and Firmicutes were the most abundant phyla in breast tissue, compared with other taxonomic groups. Authors justified these findings due to a probable host microbial adaptation to the fatty acid environment in the breast tissue.