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Review

Microbiome—Stealth Regulator of Breast Homeostasis and Cancer Metastasis

1
MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109, USA
2
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Cancers 2024, 16(17), 3040; https://doi.org/10.3390/cancers16173040
Submission received: 21 August 2024 / Revised: 29 August 2024 / Accepted: 30 August 2024 / Published: 31 August 2024
(This article belongs to the Special Issue Regulators of Breast Cancer Metastasis)

Abstract

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Simple Summary

It has long been known that breast tumors harbor various types of microbes. However, it was little known where these tumor-resident microbes came from and how they could contribute to breast cancer pathogenesis. Now, recent discoveries have unveiled that these tumor-resident microbes come from different parts of the body and live inside tumor cells to participate not only in tumorigenesis events, i.e., DNA damage and genomic instability, but also in tumor progression and metastasis. Such important findings have helped identify these intratumoral microbes as potential new targets for breast cancer treatment and prevention.

Abstract

Cumulative evidence attests to the essential roles of commensal microbes in the physiology of hosts. Although the microbiome has been a major research subject since the time of Luis Pasteur and William Russell over 140 years ago, recent findings that certain intracellular bacteria contribute to the pathophysiology of healthy vs. diseased tissues have brought the field of the microbiome to a new era of investigation. Particularly, in the field of breast cancer research, breast-tumor-resident bacteria are now deemed to be essential players in tumor initiation and progression. This is a resurrection of Russel’s bacterial cause of cancer theory, which was in fact abandoned over 100 years ago. This review will introduce some of the recent findings that exemplify the roles of breast-tumor-resident microbes in breast carcinogenesis and metastasis and provide mechanistic explanations for these phenomena. Such information would be able to justify the utility of breast-tumor-resident microbes as biomarkers for disease progression and therapeutic targets.

1. Introduction

External and internal surfaces of animal bodies are entirely covered by microorganisms. For humans, each person contains about 40 trillion microbes, which is more than the total number of 30 trillion host cells [1]. These commensals are mostly found in the gut, where their density reaches almost 10 trillion microbes per milliliter, and they weigh about one kilogram per person [2]. It is increasingly evident that these symbionts are not merely passive passengers but essential players for fundamental functions of the body, including immunity, metabolism, and energy balance [3]. This notion is well supported by the fact that germ-free (GF) mice manifest serious defects in lymphoid tissue structure and functions [4]. In particular, their gut mucosal immunity is severely compromised due to low numbers of lymphocytes and antibody production [5,6,7].
It is increasingly evident that different physiological conditions between healthy cohorts and cancer patients could be largely attributed to discrete properties of microbial floras. It is established that not only tumor microbiota but also gut microbiota of cancer patients are far less diverse than the normal counterparts—a condition of ‘dysbiosis’. Thus, correcting the microbiome of cancer patients has gained traction as an adjuvant approach [8,9,10]. For example, normalizing the microbiome of cancer patients through FMTs from healthy cohorts or treatment-responders has been proven for its therapeutic benefits. A study by Di Modica et al. reported that transferring feces from Trastuzumab responders or non-responders to antibiotic-treated mice with HER2-positive breast cancer was able to reconstitute drug responsiveness [11]. However, the detailed mechanisms of FMT-induced anti-cancer effects have not been fully elucidated.
Along with the gut microbiota, the breast microbiota is proposed to play critical roles in breast health and carcinogenesis [8,9,10]. Breast-resident microbes originate from either skin/nipple microbiota or are translocated from the gut along with immune cells, such as dendritic cells and macrophages [8,12,13]. Breast microbiota, however, could also be modified by environmental agents, such as aseptic solutions affecting skin microbiota [14]. Gut–breast microbial translocation, termed the ‘gut–breast axis’, greatly contributes to the composition of microbiota of breast tissues and milk [15,16,17,18]. This phenomenon, however, has mostly been conceived in relation to pregnancy and its influence by female sexual hormones [15,16,19,20,21,22]. Thus, it remains unclear whether the gut–breast axis exists outside pregnancy on a regular basis and contributes to breast pathophysiology. If this holds true, the gut–breast axis may contribute to FMT-mediated anti-breast cancer effects.

2. Breast Tissue Microbiota

The human breast contains a unique microbiota different from those in other parts of the body, playing critical roles in breast health as well as the health of offspring [23]. The breast tissue microbiota is more diverse (higher α-diversity) than that of skin tissue, while species’ relative abundances (Shannon indices) are similar between them [24]. Sample-to-sample differences in microbiota compositions (β-diversities) are also higher in the breast compared to the skin, owing to major differences in less abundant microbial species [24]. These features of the breast microbiota are commonly found in individuals with different ages, nationalities, and parity statuses [23]. Based on the microbiota of healthy livers or breast tumors, healthy breast-resident bacteria are expected to mostly reside inside parenchymal cells [25,26]. However, there are clear differences between healthy breast microbiota and breast tumor microbiota [24]. For example, the most abundant bacterial phyla in healthy breast tissues of women older than 18 years old are Proteobacteria and Firmicutes, whereas these bacteria are under-represented in tumors (Table 1) [27]. Many of these bacteria which are abundant in healthy breast tissues produce beneficial biomaterials that confer anti-tumor and pro-immunogenic activities to protect the healthy tissue microenvironment.

3. Breast Milk Microbiota

Breast milk microbiota are proposed to be linked to breast tissue microbiota, although there has not been any study to confirm their direct relationship. Breast milk microbiota are detectable from the third trimester of pregnancy through lactation. Breast milk, in particular colostrum (the first milk after giving birth), is the primary source of commensals to the newborn [57], whereas maternal–neonatal microbial transfers during pregnancy are conducted through the placenta and amniotic fluid [58,59]. This bacterial transfer through breast milk greatly contributes to the bacterial composition of infants’ guts, which is similar to that of breast milk [60]. The breast milk microbiota plays critical roles in the infant’s immune development and his/her health in early and later life. Thus, dysbiosis of the breast milk microbiota would greatly influence infant development [61]. Typically, a baby ingests 1 × 105 to 1 × 107 bacteria a day while consuming approximately 800 mL/day of breast milk [62]. These breast milk bacteria include the genera Lactobacillus, Staphylococcus, Enterococcus, and Bifidobacterium (Table 1) [57]. Breast milk contains olisaccharides, which are indigestible by the host but are digested by enzymes produced by specific gut bacteria, such as bifidobacterial and lactobacilli, which utilize the metabolites for their expansion [63]. In addition, breast milk contains bacterial species (e.g., Coprococcus, Faecalibacterium, and Roseburia spp) that produce short-chain fatty acids (SCFAs), such as butylate, acetate, and formic acid. These SCFA-producing bacteria repopulate the neonatal gut and play a beneficial role in weight gain and adiposity [59,64,65,66].

4. Breast Tumor Microbiota

Breast cancer is the second leading cause of cancer-related deaths in women, with about 300,000 new cases per year in the US [67]. It is a heterogeneous malignancy, and distinct molecular subtypes have been characterized, including the Luminal A subgroup expressing the hormone receptors estrogen receptor (ER) and progesterone receptor (PR); the Luminal B type expressing ER and PR plus human epidermal growth factor receptor 2 (HER2); the HER2-positive type (HER2+/ER−/PR−); and triple-negative breast cancer (TNBC; ER−/PR−/HER2−). These molecular characterizations have been primarily utilized to determine treatment regimens for specific breast cancers [68]. However, because of the frequent resistance of breast cancer to such targeted therapies [69], it is becoming clearer that other therapeutic strategies need to be developed [70], and targeting breast tumor microbiota has recently gained traction [71].
Microbes within tumors are mostly localized within tumor parenchyma as well as immune cells [26,53]. Since normal-tissue microbes are also expected to reside within parenchymal cells, they are proposed to be a major source of intratumoral microbes [72,73]. Nevertheless, breast tumor microbiota are greatly different from healthy breast microbiota, indicating substantial influences of bacterial transfer from other parts of the body during tumorigenesis (Table 1). Breast tumor microbiota are in general abundant in Fusobacterium, Atopobium, Gluconacterobacter, Hydrogenophaga, and Lactobacillus [24], unlike normal breast microbiota abundant in Proteobacteria and Firmicutes [27]. The breast tumor microbiota is associated with dysregulation of cell proliferation, metabolic pathways, and immunological responses, contributing to tumor growth and progression (Table 1) [40,45,46,74,75]. Conversely, the normal breast microbiota is associated with increased cysteine and methionine metabolism, glycosyltransferases, and fatty acid biosynthesis, promoting immunological responses [24,76,77]. Furthermore, the breast tumor microbiota is enriched in Enterobacteriaceae and Staphylococcus compared to healthy breast microbiota [27]. Both bacteria are known to produce genotoxins that induce DNA damage to help induce malignant progression of host cells [38,39]. In addition, lactic acid-producing Lactobacilli, also abundant in breast tumor microbiota, could lower pH and induce metabolic rewiring of the tumor microenvironment (TME), leading to chemotherapy and radiation resistance of tumors [78]. These three taxa of breast-tumor-associated bacteria are also found to promote tumor metastasis and colonization, being transported along with tumor cells to the metastatic site [79]. In colorectal cancer, on the contrary, a different bacterial taxon, Fusobacterium, is transported along with colon cancer cells to the metastatic site [80], suggesting the roles of different bacteria in the metastasis of different types of cancers. The involvement of breast microbiota in tumor metastasis will be further discussed below.

4.1. Breast Cancer Subtype-Specific Microbiota

Different tumor types have distinct microbial compositions, indicating the impacts of different tissues/TMEs (Table 2) [26]. Furthermore, even among breast tumors, different tumor subtypes (Luminal A, Luminal B, HER2+, and triple-negative (TN) types) have distinct microbial compositions (Table 3). This indicates that the heterogeneity of molecular and metabolic profiles and cells of origin among different breast tumor subtypes impacts the fitness of different microbial communities [56,81,82]. For example, the phyla Tenericutes, Proteobacteria, and Planctomycetes are abundant in luminal subtypes (Luminal A and B). The most abundant genus in Luminal A tumors is Xanthomonadales (phylum Proteobacteria), while that for Luminal B tumors is Clostridium (phylum Firmicutes) [83]. Conversely, HER2+ breast tumors are abundant in Akkermansia (phylum Verrucomicrobia), Thermi, Firmicutes (Filibacter, Anaerostipes, and Granulicatella_US31), Bacteroidetes (Cloacibacterium, Alloprevotella, and Dyadobacter), and Proteobacteria (Burkholderiales and Helicobacter pylori, PRD01a011B, Stakelama, and Blastomonas) [9,26,83,84,85]. In contrast, TN breast tumors are enriched in Euryarchaeota, Cyanobacteria, Firmicutes, Prevotella, Arcanobacterium, and Brevundimonas [84,86]. In particular, the presence of Listeria fleischmannii (Firmicutes) in TN tumors is shown to be strongly associated with activation of the epithelial-to-mesenchymal transition (EMT) pathway, while the presence of Haemophilus influenza (Pseudomonadota) is correlated with tumor growth and cell cycle progression [87].

4.2. Race-/Ethnicity-Specific Breast Cancer Microbiota

Racial disparity is a clinical challenge of breast cancer. Breast cancer incidence is highest among White women; however, death rates are highest among Black women, likely due to distinct features of tumors allowing their aggressive growth and metastatic progression [111]. Above all, the immunological patterns of breast tumors are largely different between races (e.g., Asian: high levels of Th1 cells (IFNγ) and megakaryocytes; White: high levels of adipocytes, hematopoietic stem cells, and endothelial cells; and Black: high levels of activated dendritic cells, B cells, mesenchymal stem cells, and CXCL9 expression) [111].
The compositions of breast tumor microbiota also vary by race, which is proposed to contribute to racial differences in other tumor properties. Smith et al. showed that Xanthomonadaceae was the most abundant member in breast tumors from Non-Hispanic White women, whereas the genus Ralstonia was most abundant in breast tumors from Non-Hispanic Black women. They also showed that tumors from Non-Hispanic White women were richer in the Bacteroidetes phylum compared to Non-Hispanic Black women [83]. Similarly, Thyagarajan et al. reported that the Bacteroidetes phylum was over-represented in TN breast tumors from White women. Conversely, in TN breast tumors from Black women, the Actinobacteria and Thermi phyla and the Bradyrhizobiaceae genus were under-represented. TN tumors from Black women also showed a reduction in Shannon diversity compared to adjacent normal tissue, while the trend was reversed for White women [112]. Furthermore, Parida et al. reported racially distinct bacterial biomarkers for breast tumors. For Asian patients, Pseudomonas, Terrabacter, Clostridiodes, Aestuariibacter, Succinimonas, Catellicoccus, Leucobacter, Rhizobium, Rhodococcus, Methylobacter, and Planctopirus are elevated; for Black patients, Xanthomonas, Amycolatopsis, Aphanizomenon, Anaerovorax, Aminiphilus, Trichormus, Chlorobium, and Sulfurovum are elevated; and for White patients: Halonatronum, Salinarchaeum, and Amorphus are elevated. Such racially different bacteria produce distinct metabolites that could regulate different miRNAs and mRNAs of hosts, contributing to different levels of metastasis predictors (e.g., lung metastasis predictors, NMU, COL2A1, PRAME, and TTYH1, are highest in breast tumors of Black women) [111,113,114].

5. Origin of Breast Tissue Microbiota

The origins of breast tissues and milk microbiota are currently unclear; however, they are proposed to be derived from the breast skin, the oral cavity of the suckling infant, and the maternal gut through the gut–breast axis (Figure 1) [58]

5.1. Microbial Transfer from Breast Skin

Mechanisms of microbial transfer from the skin to the breast have not yet been clearly determined, although there are several possible scenarios based on the transfer of pathogenic bacteria from the skin to mammary glands. Abnormal microbiota of the breast skin could contribute to the pathogenicity of breast tissue, attesting to microbial transfer from the skin to the breast tissue [14]. Skin microbes such as Pseudomonas aeruginosa possess fatty acid-metabolizing capabilities and could become pathogenic in breast tissue [115]. Additionally, Staphylococcus aureus enriched in the skin of atopic dermatitis could lead to the formation of breast abscesses also colonized by S. aureus [116]. In fact, Staphylococcus is among the most abundant genera in breast tumors and strongly linked to breast cancer metastasis, attesting to the role of skin bacteria in breast tumors [40,47,112,117]. In particular, bacteremia, or colonization of S. aureus in certain tissues, could promote the incidence of primary tumors [118,119].
Other bacterial taxa linked to increased breast cancer risk include Bacillus, Bacteroidetes, Brevundimonas, Comamonadaceae, Enterobacteriaceae, and Methylobacterium, which are also found in the skin microbiota, supporting the possibility of their transfer from the skin [47,110,112,120]. Furthermore, increased numbers of Corynebacterium and Pseudomonas, usually only found in normal skin flora, could break the skin barrier and penetrate deep into the breast tissue to induce granular lobular mastitis [121,122].
Iatrogenic breakdown of the skin barrier during medical procedures could also result in contamination of the underlying breast tissue by skin commensals [123]. For example, breast skin microbes, such as Staphylococcus epidermidis, play roles in the pathogenesis of breast-implant complications, including anaplastic large-cell lymphoma [123,124,125,126,127]. On the contrary, mechanisms of microbial transfer from the skin to the breast tissue without damage to the skin barrier are more uncertain. Proposed scenarios include retrograde transfer through the nipple and ducts (see the details below) [57] and contamination during nipple aspirate fluid procedures [110].

5.2. Microbial Transfer from the Nipple

The nipple of the mammary glands contains about ten orifices of milk ducts [128]. It was initially proposed that these ductal openings facilitate bacterial transfer from the mother’s skin into the breast milk [129]. However, this possibility was ruled out by the finding that microbial compositions of nipple skin and nipple aspirate fluid are significantly different [130]. Specifically, there are strictly anaerobic species, such as Lactobacilli and Bifidobacteria, enriched in the breast milk which are unlikely to have originated from skin microbiota [29]. As a likely mechanism of bacterial transfer through the nipples, there are some degrees of retrograde flow of milk back into the mammary glands from the infant’s mouth during suckling [57,131]. Such oscillating milk flows allow mothers to respond to pathogens afflicting infants, build antibodies for them, and transfer these antibodies back to infants so that they can fight against illnesses. Nevertheless, such retrograde bacterial transfer from infants only serves to influence, not to act as the original source of, the maternal breast microbiota. In fact, certain anerobic bacteria, such as Lactobacillus vini and L. paracasei, are more abundant in the breasts of nulliparous or never-breastfed women than in those of breastfed women [35], suggesting that these bacteria are potentially derived from the maternal gut.

5.3. Microbial Transfer via the Gut–Breast Axis or the Oro–Breast Axis

Translocation of gut bacteria to external tissues is commonly associated with disease conditions that impair the intestinal epithelial tight junctions allowing luminal bacteria to move across the epithelial barrier and get into the bloodstream [132]. However, such bacterial translocation also takes place, although to a lesser extent, in healthy individuals, involving beneficial gut bacteria such as Lactobacilli and Bifidobacteria [133,134,135]. Such non-disease-related bacterial translocation appears to involve select species and be associated with immunotraining and immunomodulation of the host [136,137,138].
During pregnancy and lactation, maternal gut bacteria translocate to the mammary glands so that they can be transferred to offsprings for colonizing their guts. During late pregnancy, there are synchronous changes in maternal mammary glands and guts. Mammary glands undergo structural and functional remodeling to become specialized organs that produce and transmit nutrients and other components necessary for neonatal growth [139]. Lactating mammary glands are also effector sites of the mucosal-associated lymphoid tissue system, playing essential roles in infants’ immunity [140]. Along with soluble immune factors, breast milk, especially colostrum, contains select types of leukocytes, such as neutrophils, macrophages, and lymphocytes [141], facilitated by the looser tight junctions of breast epithelia after giving a birth [142]. In particular, leukocytes exposed to antigens in the gut may migrate to the mammary glands and be transferred to infants through breast milk for their defense and immune training [143,144]. Synchronously, in maternal guts, epithelial permeability increases to facilitate bacterial transmigration [145]. Furthermore, the gut microbiota undergoes metabolic adaptation to elevated glucose levels, which would further modify their ability to translocate across the intestinal epithelium and reach the mammary glands [146].
Over decades, it has been known that breast milk, maternal feces, and infant feces share the same bacterial species, attesting to their physical connections [16]. Then, Perez et al. reported that a group of gut bacteria appeared to be physically translocated to mesenteric lymph nodes and then to the mammary glands during late pregnancy and lactation. Bacteria translocated to the mammary glands would then enter breast milk and be transferred to the infant to establish the microflora of the neonatal gut. Furthermore, the same study showed that viable gut bacteria found in milk-producing breast cells were also detected in peripheral blood mononuclear cells (PBMCs), indicating that PBMCs helped in the translocation of these gut bacteria to the breast [136].
The theory of gut–breast bacterial translocation was confirmed by studies demonstrating that orally administered Lactobacilli strains reached the breast milk of mothers [147,148]. Such studies also support another theory of oro–mammary bacterial translocation occasioned by the finding that maternal oral bacteria and milk microbiota partially overlap [149]. The majority of oral bacteria are expected to travel through the gastrointestinal (GI) tract to reach the gut and then be transported to the breast via the gut–breast axis. In contrast, a small fraction of oral bacteria could directly enter the oral and maxillofacial blood circulation to spread to distant tissues/organs [150]. Oro–mammary translocation is particularly important as a cause of the abundant oral bacteria (e.g., Fusobacteria and Streptococci) in breast tumors [150].

6. Mechanisms of Bacterial Translocation

Although the pathways and mechanisms by which certain bacteria enter the breast tissue have not yet been elucidated, some works have offered a plausible scientific basis. So far, there are two major mechanisms proposed: internalization/transcytosis by gut epithelia and direct sampling by phagocytic cells (Figure 2).

6.1. Internalization into Epithelial Cells

Luminal bacteria could be internalized in gut epithelial cells and subsequently taken up by dendritic cells (DCs) or macrophages in the mucosal environment. There are several potential mechanisms for the internalization of non-invasive bacteria into gut epithelial cells. First, intestinal epithelia harbor specialized microfold (M) cells that transcytose luminal bacteria to make them available to mucosal immune cells [151]. Alternatively, upon activation of TLR4, non-specialized enterocytes or kidney epithelial cells were found to transcytose Gram-negative gut bacteria [152]. Second, metabolic and oxidative stress, including hypoxia, low doses of nitric oxide, and uncoupling of mitochondrial oxidative phosphorylation, could damage the tight junctions of gut epithelia and induce transcytotic bacterial transfer to epithelia [153,154,155,156]. Third, low concentrations of IFNγ could cause the influx of noninvasive E. coli bacteria into human colon epithelia without affecting cell viability and tight junctions [157]. Such IFNγ-mediated transcytotic bacterial transfer was shown to depend on extracellular signal-regulated kinase (ERK) 1/2 and ADP-ribosylation factor (ARF)-6 [158]. Fourth, infection of intestines with the parasites Giardia lamblia or Campylobacter jejuni could damage gut epithelial barriers and tight junctions and induce penetration of luminal bacteria to the epithelia [159,160]. Fifth, viable non-pathogenic bacteria could enter host cells through endocytic pathways associated with lipid rafts and caveolin-1. Caveolin-1 or cholesterol was in fact found colocalized with bacteria-containing endosomes in epithelial cells [160,161]. These methods exploited by non-invasive bacteria are different from those of invasive pathogens that use specialized needle-like systems to inject effector proteins into epithelial cells and manipulate host cytoskeletons for anchorage and entry [162].

6.2. Sampling and Transportation by Immune Cells

It has been known that certain type of immune cells, especially those denoted as CD18+ cells, such as DCs and macrophages, could penetrate the gut epithelial barrier and directly take up non-pathogenic commensal bacteria from the lumen [163,164]. DCs especially are capable of opening tight junctions of intestinal epithelia and sampling luminal bacteria without destroying epithelial integrity because of their ability to repair damage. This allows non-invasive gut bacteria to spread to extraintestinal organs [163]. Similarly, macrophages could promote the extraintestinal dissemination of non-invasive gut bacteria [164]. It was shown that induction of DCs with viable commensal bacteria, but not dead bacteria, stimulates DC maturation, indicated by the increase in the class II major histocompatibility complex (MHC) and the B7.2 protein on the cell surface, and their translocation across the colon epithelium [165,166,167]. DCs, and possibly macrophages, that have taken up luminal bacteria would migrate to the nearby mesenteric lymph nodes and stay there for up to several days [168]. Such lymphoid-tissue-resident gut commensals are found to elevate anti-inflammatory signaling to help establish mutualism with host immunity [169]. Alternatively, these lymphoid-resident gut commensals could be taken up by lymphocytes and transported to distant tissues, such as lactating mammary glands [170,171]. In lactating mammary glands, the colonization of immune cells and their bacteria cargos is selective due to regulation by lactogenic hormones and retrograde signaling from suckling infants requesting specific immune cells to fight against their ailments [141,172,173].

7. Functions of Intracellular Microbiota

Increasing evidence demonstrates the existence of different intracellular bacteria in humans and mice [174,175,176,177]. The prevalence of intracellular bacteria over extracellular bacteria in tissues is largely attributed to more efficient immunological clearance of the latter than the former [178]. These intracellular microbes are proposed to play direct roles in the pathophysiology of normal tissues and tumors [179]. This view has been increasingly solidified since the groundbreaking discoveries of the roles of Helicobacter pylori in stomach ulcers and gastric cancer 30 years ago [180]. The recent surge in next-generation sequencing technologies has allowed investigators to profile microbial compositions of tumor tissues, identify tumor-associated microbes, and study their specific functions. Certain commensal bacteria invade cancer cells and remain inside cells during tumor progression and even metastasis [80,179]. This is largely attributed to the fact that intracellular bacteria are better protected than extracellular bacteria in a highly immunologic TME [79].

8. Bacterially Produced Metabolites

As discussed above, microbiota in human breast milk and breast tissue play essential roles in infants’ development and healthy intestinal microbiota and immunity. In particular, different bacterially produced metabolites contribute to differences in breast tissue microenvironments and the health of offspring [19]. A group of bacterially produced metabolites have been found to exert beneficial effects. For example, short-chain fatty acids (SCFAs), such as butyrate, acetate, and formic acid, in breast milk promote weight gain and adiposity in infants [66]. Cadaverine, a metabolite produced by bacterial lysine decarboxylase, is found to suppress breast cancer progression and metastasis, although the synthesis is downmodulated in breast cancer patients [181]. Also, indolepropionic acid (IPA) is a bacterial tryptophan metabolite that has cytostatic properties through activation of aryl hydrocarbon and pregnane X receptors. Ectopic application of IPA to breast cancer cells has been found to suppress their growth and metastasis [182]. On the other hand, another group of bacteria-derived metabolites exacerbate breast cancer growth. For example, queuine is a nucleobase mostly synthesized by certain pathogenic bacteria, such as Clostridioides difficile and Chlamydia trachomatis, to promote their virulence. Queuine is incorporated into specific transfer RNAs (tRNAs) which drive the expression of genes involved in cell proliferation and migration of breast cancer cells [183,184]. Furthermore, recent studies report anti-tumor effects of the bacterial metabolite trimethylamine N-oxide (TMAO), produced by a group of commensal bacteria, such as Clostridia, Bifidobacteria, and Coriobacteria. TMAO could promote the tumor-cell-killing activities of CD8+ T cells and M1-type macrophages. Analysis of clinical tumor samples found that TNBC tumors abundant in Clostridiales are enriched in TMAO and exhibit activated immune microenvironments [185].

9. Breast-Tumor-Associated Bacteria

The different levels of bacterial metabolites in normal vs. cancerous breast tissues discussed above are largely attributed to differences in microbial compositions. Decreased ratios of Sphingomonas yanoikuyae to Methylobacterium radiotolerans in the breast tissues are linked to elevated breast cancer risks [110]. Lactobacillus, Staphylococcus, and Enterobacteriaceae are more abundant in tumor-adjacent normal breast tissues compared to healthy breast tissues, indicating their contributions to neoplastic processes [47]. These different tumor-associated bacteria play differential roles in the development of breast cancer. Pro- and anti-tumor roles of select commensal bacteria are discussed below.

9.1. Origin of Breast-Tumor-Resident Bacteria

Breast-tumor-resident bacteria are proposed to have similar origins to those in normal breast tissues, namely, breast skin, the oral cavity of the suckling infant, the maternal gut through the gut–breast axis, and the maternal oral cavity through the oro–breast axis [186]. However, how these bacteria have traveled to distant tumors remains largely unknown. Bacterial strains found in tumors are mostly present in the gut microbiome, supporting the possibility of the gut–breast axis [187]. The oral microbiota is also one of the potential sources of breast-tumor-resident bacteria [188]. In particular, Fusobacterium nucleatum, a major human oral bacterium, is commonly found in breast tumor cells [30], while it is rarely found in the intestine and thus is expected to reach tumors through the circulatory system [189]. Furthermore, a study by Nejman et al. showed that bacteria in tumor-adjacent normal breast tissues had intermediate compositions between those of breast tumors and normal tissues [26]. This indicates that there are bacterial transfers between neighboring tissues that result in heterogeneity within tumors.

9.2. Major Breast-Tumor-Resident Bacterial Species

There are several major bacterial species frequently found in breast tumor samples.

9.2.1. Fusobacterium nucleatum

Fusobacterium nucleatum is a common opportunistic bacterium in the oral cavity and is a potential causative agent of periodontitis and oral carcinomas [190]. This bacterium is also elevated in various types of solid tumors, especially in colorectal tumors, compared to matched healthy tissues [191]. It is also associated with liver metastasis, indicating the broad spread of this oral pathogen [80]. F. nucleatum localizes at tumor sites by attaching to cell-surface galactose-N-acetylgalactosamine (Gal-GalNAc) through its lectin Fap2 [29,179]. In particular, intravascularly injected Fap2-expressing F. nucleatum strain ATCC 23726 specifically colonizes mammary tumors in mice, whereas Fap2-deficient bacteria fail to do so. Furthermore, F. nucleatum secretes an amyloid-like filament FadA which not only helps the attachment and invasion of the bacterium to host cells [192], but also serves as the scaffold of biofilm formation and promotes cancer progression [193]. Within tumor cells, F. nucleatum induces pro-inflammatory signaling through the TNFα, NF-kB, and IL-6/IL-8 pathways [194,195,196] and promotes tumor growth, EMT, metastasis, and therapy resistance, while also suppressing NK cell-mediated tumor cell killing and T cell infiltration into tumors [29,98].

9.2.2. Streptococcus

Streptococcus is an oral bacterium found to promote metastasis and colonization of metastasized breast cancer cells [79]. Streptococcus mutans is a Gram-positive bacterium associated with dental caries (cavities). This bacterium could invade endothelial cells through Toll-like receptor 2, which triggers the production of pro-inflammatory IL-6/IL-8 and monocyte chemoattractant protein-1 (MCP1). Inflamed endothelial cells elevate the permeability of blood vessels, leading to various systemic conditions. For example, intravenously injected S. mutans has been shown to induce lung vascular inflammation (e.g., thrombosis) and promote breast cancer metastasis to the lungs [197,198]. In addition, S. cuniculiIn, originally isolated from the respiratory tract of wild animals [199], has been shown to promote the metastatic potential of tumor cells by reorganizing actin cytoskeletons to resist shear stress during invasion [79]. In contrast, another strain of Streptococci confers beneficial effects on breast cancer treatment. S. salivarius, an abundant probiotic bacterium found in breast milk, has been shown to suppress breast cancer growth when applied ectopically. Similarly, S. pneumoniae, the bacterium responsible for pneumonia and lung cancer [200], produces endopeptidase O (PepO) virulence protein. Ectopic administration of PepO to a mouse model of triple-negative breast cancer (TNBC) has been shown to activate TLR2/4 in tumor-associated macrophages and suppresses breast tumor growth [201].

9.2.3. Staphylococcus and Enterobacteriaceae

Staphylococcus and Enterobacteriaceae are intestinal bacteria that could induce DNA damage within host cells. Staphylococci produce a toxin, alpha phenol-soluble modulin (PSMα), and specific lipoproteins (Lpls). PSMα could induce DNA damage, whereas Lpls dampen DNA damage repair signaling, compromising the genomic integrity of the host cell [39]. Furthermore, S. aureus, a bacterium usually found in the upper respiratory tract and the skin, lowers the immunogenicity of the TME by suppressing effector T cells and promoting regulatory T cells [202]. In addition, S. xylosus, a skin commensal, promotes the metastatic potential of tumor cells by reorganizing actin cytoskeletons to resist fluid shear stress (FSS) during invasion [79]. Enterobacteriaceae (e.g., E. coli and Salmonella) are mostly intestinal commensals, and systemic infection with these bacteria is a common complication in cancer patients [203]. Similar to Staphylococcus, Enterobacteriaceae, especially those harboring the polyketide synthase (pks) island, produce a genotoxin, Colibactin, that causes DNA double-strand breaks [204]. Enterobacteriaceae also impair the expression of p53 tumor suppressor upon DNA damage, contributing to genomic instability of the host cell [205]. Furthermore, Enterobacteriaceae-infected host tumor cells produce bactericidal lysophosphatidylcholines, which have been found to be elevated in breast tumors and promote tumor growth and metastasis [206,207].

9.3. Roles of Intracellular Microbes in Breast Tumor Initiation/Development

According to the International Agency for Research on Cancer (IARC), 18–20% of cancers are caused by biological carcinogens such as oncogenic viruses and bacteria [208]. The roles of these microbes in cancer initiation and development involve six major mechanisms: genome instability/mutation, epigenetic modification, chronic inflammation, immune evasion, metabolic regulation, and metastasis [209]. Among these, we will specifically focus on the roles of microbes in genome instability/mutation and metastasis.

9.3.1. Genome Instability/Mutation

The induction of genomic instability and mutation is one of the major carcinogenic mechanisms of microbes. Oncoviruses are some of the major breast-tumor-causing agents, including human papilloma virus (HPV), mouse mammary tumor virus (MMTV), Epstein–Barr virus (EBV), and bovine leukemia virus (BLV) [210]. They integrate the viral genome into the host chromosome to induce genetic mutations, while oncoproteins are produced by the integrated viral genome. For example, the HPV E7 oncoprotein directly inhibits the cGas-STING pathway involved in the expression of type I interferon and pro-inflammatory factors, leading to immune escape [211,212]. EBV LMP1 oncoprotein upregulates oncogenic signaling pathways, such as the NF-κB pathway, involved in cell proliferation [213], while MMTV oncovirus-infected cells escape apoptosis by activation of the Src tyrosine kinase pathway [214].
Likewise, certain carcinogenic bacteria, such as pks+ Escherichia coli and Bacteroides fragilis, secrete carcinogenic toxins that induce DNA damage, which results in elevated tumor onset and mortality [215]. The toxin produced by Bacteroides fragilis also promotes the expression of the enzyme spermine oxidase, producing reactive oxygen species (ROS) that cause DNA damage [216]. The oncobacterium Fusobacterium nucleatum secretes FadA, a key adhesin, that activates the E-cadherin/β-catenin pathway to upregulate checkpoint kinase 2 (CHK2), inducing DNA damage [217]. Fusobacterium nucleatum infection also downmodulates the Ku70/p53 DNA damage repair pathway, exacerbating DNA double-strand breaks (DSBs) [218]. E. coli and Staphylococcus epidermis isolated from breast tumors could cause DSBs even in cervical cancer cells, demonstrating non-tissue-specific tumorigenicity [47]. Furthermore, H. pylori and E. coli expressing EspF effector protein could suppress DNA mismatch repair mechanisms, augmenting genome instability and tumorigenesis [215,219].
Bacterial metabolites could also induce DNA damage to promote tumor development. Breast tumor tissues contain elevated levels of β-glucuronidase, a carcinogenic enzyme [130,220], that generates reactive intermediates from 2-amino-3-methylimidazo [4,5-f]quinoline to induce DNA damage [221]. Furthermore, Streptococcus anginosus and Porphyromonas gingivalis can convert ethanol to acetaldehyde, which could form DNA adducts or inhibit DNA repair enzymes, causing DNA damage [222,223].

9.3.2. Tumor Metastasis

Over the past decade, it has been unveiled that intratumoral bacteria play critical roles in tumor metastasis. The initial study by Bullman et al. reported that primary colorectal tumors and their metastases shared the same viable bacterial components and that these bacteria were able to promote tumor cell growth and survival [80]. Furthermore, recent studies demonstrated that these tumor-resident bacteria are in fact localized in the cytosol of tumor cells and transported to metastatic sites by tumor cells. During tumor cell metastasis, the intracellular bacteria promote tumor cell survival by allowing them to overcome physical and biochemical hurdles in unfavorable environments through adaptations termed pro-metastatic processes [72,79,224]. During pro-metastatic adaptations, tumor cells acquire capabilities of breaking tissue boundaries, controlling the local environment, conferring immune suppression and resistance to mechanical stress, and remodulating tumor cell intrinsic properties, such as EMT, stemness, and adhesion (Figure 3) [224]. Here are some examples of intratumoral bacteria playing roles in the pro-metastasis and metastasis of tumor cells.
Listeria food bacteria, in particular Listeria monocytogenes, are intracellular pathogens found in decaying food [225]. L. monocytogenes has been long utilized to develop cancer vaccines because it induces potent innate and adaptive immunological responses [226]. However, this bacterium could also reside within breast tumor cells and promote the growth and metastasis of tumor cells, worsening the prognoses of patients [227,228]. Intratumoral L. monocytogenes induces cytoskeletal reorganization of tumor cells through its actin nucleation protein ActA and promotes tumor cell survival under FSS in the circulation [228]. Furthermore, such actin nucleation also recruits the ubiquitin-conjugating enzyme Ube2N that activates TAK1-p38 MAP kinase signaling that controls tumor cell metastasis [229,230]. Not only the pathogenic strain, but also a non-pathogenic strain, L. fleischmannii, resides within breast tumors and is strongly associated with elevated expression of EMT-associated genes [87].
Another tumor-metastasis-associated bacterium is Fusobacterium nucleatum, an opportunistic bacterium usually found in the oral cavity but which is also abundant in breast tumors [29]. Intratumoral F. nucleatum promotes tumor cell invasion and suppresses immunological response through several different mechanisms [29]. First, F. nucleatum produces a virulence factor, FadA, an amyloid protein that helps the binding of the pathogen to host cells [231]. FadA upregulates Mir4435-2HG, which then induces the expression of SNAIL1 triggering EMT of host cells [98]. Second, F. nucleatum elevates the expression of MMP-9, which degrades the extracellular matrix to assist tumor cell invasion. Third, F. nucleatum upregulates the expression of an adhesion molecule, ICAM1, through the ALPK1/NF-κB axis that promotes tumor cell adhesion to endothelial cells during intravasation [232]. Fourth, F. nucleatum induces the production of extracellular vesicles that promote the expression of TLR4 in neighboring tumor cells to help their growth and metastasis [233]. Fifth, F. nucleatum elevates the expression of immune checkpoint receptors, TIGIT and CEACAM1, that suppress immunological responses. Lastly, F. nucleatum directly invades and kills tumor-infiltrating lymphocytes, including NK cells and T cells [29].
The third tumor-metastasis-associated bacterium is Bacteroides fragilis, an abundant commensal bacterium in colon and breast tumors. B. fragilis produces an enterotoxin, B. fragilis toxin (BFT), a zinc-dependent metalloprotease commonly associated with inflammatory colon diseases. Intratumorally produced BFT could elevate the growth and metastatic potential of breast tumor cells by inducing the expression of stem cell-/EMT-associated genes such as Slug and Twist [111,234,235]. Regarding the mechanisms of this phenomenon, it has been shown that BFT induces the cleavage of E-cadherin on the surface of tumor cells, which then triggers nuclear localization of β-catenin and Notch effector NICD. Activation of both the Wnt and Notch signaling pathways greatly promotes stemness and metastasis in tumors [236].
Furthermore, Staphylococcus and Lactibacillus, commensal bacteria abundant in breast tumor cells, have been shown to translocate to the lungs along with metastasizing tumor cells. These intracellular bacteria inhibit RhoA/ROCK-induced contractility of tumor cells while being exposed to FSS, conferring protection against mechanical-force-induced apoptosis of tumor cells during metastasis [79]. As a potential mechanism, the same group proposed the possible involvement of ADP-ribosyltransferase C3 exoenzyme produced by these bacteria. This enzyme inhibits Rho GTPases to counteract immune cell activities and is well studied as a virulence factor of select bacterial species, such as Staphylococcus and Bacilus [237,238].

10. Discussion

Cumulative evidence unveils that intratumoral microbes are not only mere biomarkers for breast cancer phenotype and prognosis, but also the causes of breast cancer initiation and metastasis. Such roles of intratumoral microbes suggest that they could serve as potential targets for breast cancer treatment and prevention. Thus, the efficacy of antibiotics in combination with chemotherapy has been tested for breast cancer treatment. However, these antibiotics are reported to show both positive and negative effects, depending on whether they target tumor-resident bacteria or intestinal microbes [239]. For example, a Phase II study combining Moxifloxacin, a fourth-generation quinolone with broad-spectrum coverage of breast-tumor-resident bacteria, and a treatment of the physician’s choice (TPC; capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) reported a promising efficacy and well-tolerated toxicities in patients with metastatic breast cancer [240]. On the other hand, a retrospective study on 772 women with triple-negative breast cancer treated with antimicrobials along with standard cytotoxic chemotherapy found that these patients had overall poorer survival than those without antimicrobials [241]. Such deleterious effects of antimicrobial use for breast cancer patients are largely due to intestinal microbiota disorders that impair immune function and trigger a systemic inflammatory response [239]. One possible solution to such a conundrum is to repopulate beneficial bacterial flora by supplementing probiotics and prebiotics to cancer patients treated with antibiotics. Furthermore, more recent strategies include fecal matter transplant from healthy cohorts to patients with breast cancer resistant to standard chemotherapy. Therapeutic manipulation of the tumor microbiome is an emerging research field which will revolutionize cancer therapy in the near future.

11. Conclusions

In summary, recent studies have unveiled that intratumoral microbes play critical roles in breast cancer development and metastasis, serving as potential biomarkers and therapeutic targets for the disease. Furthermore, given that these pro-tumor bacteria are likely derived from other parts of the body, including the skin and oral cavity, a future endeavor aiming to prevent their colonization and translocation to the breast tissue would warrant further investigation as a novel strategy for breast cancer prevention.

Funding

This work was supported by the startup fund of the Department of Medicine, MetroHealth Medical Center/Case Western Reserve University, with an award to S.F.; an American Cancer Society Research Scholar Grant (RSG-18-238-01-CSM) awarded to S.F.; and National Cancer Institute Research Grants (R01CA248304 and R21CA288449) awarded to S.F.

Data Availability Statement

All data generated or analyzed during this study are included in the published article.

Acknowledgments

The author would like to thank all the laboratory members of the Furuta laboratory at MetroHealth Medical Center/Case Western Reserve University for constructive suggestions regarding the subject matter of the manuscript.

Conflicts of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

References

  1. Sender, R.; Fuchs, S.; Milo, R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 2016, 164, 337–340. [Google Scholar] [CrossRef] [PubMed]
  2. Goodrich, J.K.; Davenport, E.R.; Clark, A.G.; Ley, R.E. The Relationship Between the Human Genome and Microbiome Comes into View. Annu. Rev. Genet. 2017, 51, 413–433. [Google Scholar] [CrossRef]
  3. Smith, K.; McCoy, K.D.; Macpherson, A.J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 2007, 19, 59–69. [Google Scholar] [CrossRef] [PubMed]
  4. Zheng, D.; Liwinski, T.; Elinav, E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020, 30, 492–506. [Google Scholar] [CrossRef] [PubMed]
  5. Umesaki, Y.; Setoyama, H.; Matsumoto, S.; Okada, Y. Expansion of alpha beta T-cell receptor-bearing intestinal intraepithelial lymphocytes after microbial colonization in germ-free mice and its independence from thymus. Immunology 1993, 79, 32–37. [Google Scholar]
  6. Hapfelmeier, S.; Lawson, M.A.; Slack, E.; Kirundi, J.K.; Stoel, M.; Heikenwalder, M.; Cahenzli, J.; Velykoredko, Y.; Balmer, M.L.; Endt, K.; et al. Reversible microbial colonization of germ-free mice reveals the dynamics of IgA immune responses. Science 2010, 328, 1705–1709. [Google Scholar] [CrossRef]
  7. Ivanov, I.I.; Frutos, R.d.L.; Manel, N.; Yoshinaga, K.; Rifkin, D.B.; Sartor, R.B.; Finlay, B.B.; Littman, D.R. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 2008, 4, 337–349. [Google Scholar] [CrossRef]
  8. Di Modica, M.; Arlotta, V.; Sfondrini, L.; Tagliabue, E.; Triulzi, T. The Link Between the Microbiota and HER2+ Breast Cancer: The New Challenge of Precision Medicine. Front. Oncol. 2022, 12, 947188. [Google Scholar] [CrossRef]
  9. Tzeng, A.; Sangwan, N.; Jia, M.; Liu, C.-C.; Keslar, K.S.; Downs-Kelly, E.; Fairchild, R.L.; Al-Hilli, Z.; Grobmyer, S.R.; Eng, C. Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer. Genome Med. 2021, 13, 60. [Google Scholar] [CrossRef]
  10. Bodai, B.I.; Nakata, T.E. Breast Cancer: Lifestyle, the Human Gut Microbiota/Microbiome, and Survivorship. Perm. J. 2020, 24, 19.129. [Google Scholar] [CrossRef]
  11. Di Modica, M.; Gargari, G.; Regondi, V.; Bonizzi, A.; Arioli, S.; Belmonte, B.; De Cecco, L.; Fasano, E.; Bianchi, F.; Bertolotti, A.; et al. Gut Microbiota Condition the Therapeutic Efficacy of Trastuzumab in HER2-Positive Breast Cancer. Cancer Res. 2021, 81, 2195–2206. [Google Scholar] [CrossRef] [PubMed]
  12. Sepich-Poore, G.D.; Zitvogel, L.; Straussman, R.; Hasty, J.; Wargo, J.A.; Knight, R. The microbiome and human cancer. Science 2021, 371, eabc4552. [Google Scholar] [CrossRef] [PubMed]
  13. Nagpal, R.; Yadav, H. Bacterial Translocation from the Gut to the Distant Organs: An Overview. Ann. Nutr. Metab. 2017, 71 (Suppl. 1), 11–16. [Google Scholar] [CrossRef] [PubMed]
  14. Wang, K.; Nakano, K.; Naderi, N.; Bajaj-Elliott, M.; Mosahebi, A. Is the skin microbiota a modifiable risk factor for breast disease?: A systematic review. Breast 2021, 59, 279–285. [Google Scholar] [CrossRef] [PubMed]
  15. Selvamani, S.; Dailin, D.J.; Gupta, V.K.; Wahid, M.; Keat, H.C.; Natasya, K.H.; Malek, R.A.; Haque, S.; Sayyed, R.Z.; Abomoelak, B.; et al. An Insight into Probiotics Bio-Route: Translocation from the Mother’s Gut to the Mammary Gland. Appl. Sci. 2021, 11, 7247. [Google Scholar] [CrossRef]
  16. Rodríguez, J.M.; Fernández, L.; Verhasselt, V. The Gut–Breast Axis: Programming Health for Life. Nutrients 2021, 13, 606. [Google Scholar] [CrossRef]
  17. Farache, J.; Koren, I.; Milo, I.; Gurevich, I.; Kim, K.W.; Zigmond, E.; Furtado, G.C.; Lira, S.A.; Shakhar, G. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 2013, 38, 581–595. [Google Scholar] [CrossRef]
  18. Soto-Pantoja, D.R.; Gaber, M.; Arnone, A.A.; Bronson, S.M.; Cruz-Diaz, N.; Wilson, A.S.; Clear, K.Y.J.; Ramirez, M.U.; Kucera, G.L.; Levine, E.A.; et al. Diet Alters Entero-Mammary Signaling to Regulate the Breast Microbiome and Tumorigenesis. Cancer Res. 2021, 81, 3890–3904. [Google Scholar] [CrossRef]
  19. Zhang, J.; Xia, Y.; Sun, J. Breast and gut microbiome in health and cancer. Genes Dis. 2021, 8, 581–589. [Google Scholar] [CrossRef]
  20. Flood, T.R.; Kuennen, M.R.; Blacker, S.D.; Myers, S.D.; Walker, E.F.; Lee, B.J. The effect of sex, menstrual cycle phase and oral contraceptive use on intestinal permeability and ex-vivo monocyte TNFα release following treatment with lipopolysaccharide and hyperthermia. Cytokine 2022, 158, 155991. [Google Scholar] [CrossRef]
  21. Atashgaran, V.; Wrin, J.; Barry, S.C.; Dasari, P.; Ingman, W.V. Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk. Front. Oncol. 2016, 6, 267. [Google Scholar] [CrossRef] [PubMed]
  22. Schaadt, N.S.; Alfonso, J.C.L.; Schönmeyer, R.; Grote, A.; Forestier, G.; Wemmert, C.; Krönke, N.; Stoeckelhuber, M.; Kreipe, H.H.; Hatzikirou, H.; et al. Image analysis of immune cell patterns in the human mammary gland during the menstrual cycle refines lymphocytic lobulitis. Breast Cancer Res. Treat. 2017, 164, 305–315. [Google Scholar] [CrossRef]
  23. Younes, J.A.; Lievens, E.; Hummelen, R.; van der Westen, R.; Reid, G.; Petrova, M.I. Women and Their Microbes: The Unexpected Friendship. Trends Microbiol. 2018, 26, 16–32. [Google Scholar] [CrossRef]
  24. Hieken, T.J.; Chen, J.; Hoskin, T.L.; Walther-Antonio, M.; Johnson, S.; Ramaker, S.; Xiao, J.; Radisky, D.C.; Knutson, K.L.; Kalari, K.R.; et al. The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease. Sci. Rep. 2016, 6, 30751. [Google Scholar] [CrossRef]
  25. Sun, X.W.; Zhang, H.; Zhang, X.; Xin, P.F.; Gao, X.; Li, H.R.; Zhou, C.Y.; Gao, W.M.; Kou, X.X.; Zhang, J.G. Liver Microbiome in Healthy Rats: The Hidden Inhabitants of Hepatocytes. Cell. Microbiol. 2023, 2023, 7369034. [Google Scholar] [CrossRef]
  26. Nejman, D.; Livyatan, I.; Fuks, G.; Gavert, N.; Zwang, Y.; Geller, L.T.; Rotter-Maskowitz, A.; Weiser, R.; Mallel, G.; Gigi, E.; et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 2020, 368, 973–980. [Google Scholar] [CrossRef]
  27. Urbaniak, C.; Cummins, J.; Brackstone, M.; Macklaim, J.M.; Gloor, G.B.; Baban, C.K.; Scott, L.; O’Hanlon, D.M.; Burton, J.P.; Francis, K.P.; et al. Microbiota of Human Breast Tissue. Appl. Environ. Microbiol. 2014, 80, 3007–3014. [Google Scholar] [CrossRef] [PubMed]
  28. Lawani-Luwaji, E.U.; Alade, T. Sphingomonadaceae: Protective against breast cancer? Bull. Natl. Res. Cent. 2020, 44, 191. [Google Scholar] [CrossRef]
  29. Parhi, L.; Alon-Maimon, T.; Sol, A.; Nejman, D.; Shhadeh, A.; Fainsod-Levi, T.; Yajuk, O.; Isaacson, B.; Abed, J.; Maalouf, N.; et al. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat. Commun. 2020, 11, 3259. [Google Scholar] [CrossRef]
  30. Little, A.; Tangney, M.; Tunney, M.M.; Buckley, N.E. Fusobacterium nucleatum: A novel immune modulator in breast cancer? Expert Rev. Mol. Med. 2023, 25, e15. [Google Scholar] [CrossRef]
  31. Brook, I. Chapter 173—Anaerobic bacteria. In Infectious Diseases, 3rd ed.; Cohen, J., Opal, S.M., Powderly, W.G., Eds.; Mosby: London, UK, 2010; pp. 1757–1776. [Google Scholar]
  32. Allali, I.; Delgado, S.; Marron, P.I.; Astudillo, A.; Yeh, J.J.; Ghazal, H.; Amzazi, S.; Keku, T.; Azcarate-Peril, M.A. Gut microbiome compositional and functional differences between tumor and non-tumor adjacent tissues from cohorts from the US and Spain. Gut Microbes 2015, 6, 161–172. [Google Scholar] [CrossRef] [PubMed]
  33. An, J.; Kwon, H.; Kim, Y.J. The Firmicutes/Bacteroidetes Ratio as a Risk Factor of Breast Cancer. J. Clin. Med. 2023, 12, 2216. [Google Scholar] [CrossRef] [PubMed]
  34. Hieken, T.J.; Chen, J.; Chen, B.; Johnson, S.; Hoskin, T.L.; Degnim, A.C.; Walther-Antonio, M.R.; Chia, N. The breast tissue microbiome, stroma, immune cells and breast cancer. Neoplasia 2022, 27, 100786. [Google Scholar] [CrossRef]
  35. German, R.; Marino, N.; Hemmerich, C.; Podicheti, R.; Rusch, D.B.; Stiemsma, L.T.; Gao, H.; Xuei, X.; Rockey, P.; Storniolo, A.M. Exploring breast tissue microbial composition and the association with breast cancer risk factors. Breast Cancer Res. 2023, 25, 82. [Google Scholar] [CrossRef] [PubMed]
  36. Yao, Z.; Ma, Q.; Cai, Z.; Raza, M.F.; Bai, S.; Wang, Y.; Zhang, P.; Ma, H.; Zhang, H. Similar Shift Patterns in Gut Bacterial and Fungal Communities Across the Life Stages of Bactrocera minax Larvae from Two Field Populations. Front. Microbiol. 2019, 10, 2262. [Google Scholar] [CrossRef] [PubMed]
  37. Urbaniak, C.; McMillan, A.; Angelini, M.; Gloor, G.B.; Sumarah, M.; Burton, J.P.; Reid, G. Effect of chemotherapy on the microbiota and metabolome of human milk, a case report. Microbiome 2014, 2, 24. [Google Scholar] [CrossRef]
  38. Boopathi, S.; Priya, P.S.; Haridevamuthu, B.; Nayak, S.P.R.R.; Chandrasekar, M.; Arockiaraj, J.; Jia, A.-Q. Expanding germ-organ theory: Understanding non-communicable diseases through enterobacterial translocation. Pharmacol. Res. 2023, 194, 106856. [Google Scholar] [CrossRef]
  39. Deplanche, M.; Mouhali, N.; Nguyen, M.-T.; Cauty, C.; Ezan, F.; Diot, A.; Raulin, L.; Dutertre, S.; Langouet, S.; Legembre, P.; et al. Staphylococcus aureus induces DNA damage in host cell. Sci. Rep. 2019, 9, 7694. [Google Scholar] [CrossRef]
  40. Klann, E.; Williamson, J.M.; Tagliamonte, M.S.; Ukhanova, M.; Asirvatham, J.R.; Chim, H.; Yaghjyan, L.; Mai, V. Microbiota composition in bilateral healthy breast tissue and breast tumors. Cancer Causes Control. 2020, 31, 1027–1038. [Google Scholar] [CrossRef]
  41. Wahid, M.; Dar, S.A.; Jawed, A.; Mandal, R.K.; Akhter, N.; Khan, S.; Khan, F.; Jogaiah, S.; Rai, A.K.; Rattan, R. Microbes in gynecologic cancers: Causes or consequences and therapeutic potential. Semin. Cancer Biol. 2022, 86, 1179–1189. [Google Scholar] [CrossRef]
  42. Nakajima-Adachi, H.; Tamai, M.; Nakanishi, H.; Hachimura, S. Extracts of Gluconacetobacter hansenii GK-1 induce Foxp3(+)T cells in food-allergic mice by an IL-4-dependent or IL-4-independent mechanism. Biosci. Microbiota Food Health 2022, 41, 137–144. [Google Scholar] [CrossRef] [PubMed]
  43. Lilian, M.; Rawlynce, B.; Charles, G.; Felix, K. Potential role of rumen bacteria in modulating milk production and composition of admixed dairy cows. Lett. Appl. Microbiol. 2023, 76, ovad007. [Google Scholar] [CrossRef]
  44. Sangeetha, M.; Menakha, M.; Vijayakumar, S. Cryptophycin F—A potential cyanobacterial drug for breast cancer. Biomed. Aging Pathol. 2014, 4, 229–234. [Google Scholar] [CrossRef]
  45. Yang, Y.; Fukui, R.; Jia, H.; Kato, H. Amaranth Supplementation Improves Hepatic Lipid Dysmetabolism and Modulates Gut Microbiota in Mice Fed a High-Fat Diet. Foods 2021, 10, 1259. [Google Scholar] [CrossRef] [PubMed]
  46. Milton-Laskibar, I.; Cuevas-Sierra, A.; Portillo, M.P.; Martínez, J.A. Effects of Resveratrol Administration in Liver Injury Prevention as Induced by an Obesogenic Diet: Role of Ruminococcaceae. Biomedicines 2022, 10, 1797. [Google Scholar] [CrossRef] [PubMed]
  47. Urbaniak, C.; Gloor, G.B.; Brackstone, M.; Scott, L.; Tangney, M.; Reid, G. The Microbiota of Breast Tissue and Its Association with Breast Cancer. Appl. Env. Microbiol. 2016, 82, 5039–5048. [Google Scholar] [CrossRef]
  48. Bindels, L.B.; Porporato, P.; Dewulf, E.M.; Verrax, J.; Neyrinck, A.M.; Martin, J.C.; Scott, K.P.; Buc Calderon, P.; Feron, O.; Muccioli, G.G.; et al. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br. J. Cancer 2012, 107, 1337–1344. [Google Scholar] [CrossRef]
  49. Dong, Y.; Zhang, K.; Wei, J.; Ding, Y.; Wang, X.; Hou, H.; Wu, J.; Liu, T.; Wang, B.; Cao, H. Gut microbiota-derived short-chain fatty acids regulate gastrointestinal tumor immunity: A novel therapeutic strategy? Front. Immunol. 2023, 14, 1158200. [Google Scholar] [CrossRef]
  50. Derqaoui, S.; Oukessou, M.; Attrassi, K.; Elftouhy, F.Z.; Nassik, S. Detection of Sutterella spp. in Broiler Liver Breast. Front. Vet. Sci. 2022, 9, 859902. [Google Scholar] [CrossRef]
  51. Gutierrez-Orozco, F.; Thomas-Ahner, J.M.; Galley, J.D.; Bailey, M.T.; Clinton, S.K.; Lesinski, G.B.; Failla, M.L. Intestinal microbial dysbiosis and colonic epithelial cell hyperproliferation by dietary α-mangostin is independent of mouse strain. Nutrients 2015, 7, 764–784. [Google Scholar] [CrossRef]
  52. Thu, M.S.; Chotirosniramit, K.; Nopsopon, T.; Hirankarn, N.; Pongpirul, K. Human gut, breast, and oral microbiome in breast cancer: A systematic review and meta-analysis. Front. Oncol. 2023, 13, 1144021. [Google Scholar]
  53. Wang, M.; Yu, F.; Li, P. Intratumor microbiota in cancer pathogenesis and immunity: From mechanisms of action to therapeutic opportunities. Front. Immunol. 2023, 14, 1269054. [Google Scholar] [CrossRef] [PubMed]
  54. Gao, F.; Yu, B.; Rao, B.; Sun, Y.; Yu, J.; Wang, D.; Cui, G.; Ren, Z. The effect of the intratumoral microbiome on tumor occurrence, progression, prognosis and treatment. Front. Immunol. 2022, 13, 1051987. [Google Scholar] [CrossRef] [PubMed]
  55. Li, Y.; Ren, L.; Wang, Y.; Li, J.; Zhou, Q.; Peng, C.; Li, Y.; Cheng, R.; He, F.; Shen, X. The Effect of Breast Milk Microbiota on the Composition of Infant Gut Microbiota: A Cohort Study. Nutrients 2022, 14, 5397. [Google Scholar] [CrossRef]
  56. Dieleman, S.; Aarnoutse, R.; Ziemons, J.; Kooreman, L.; Boleij, A.; Smidt, M. Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response. Am. J. Pathol. 2021, 191, 968–982. [Google Scholar] [CrossRef]
  57. Fernández, L.; Langa, S.; Martín, V.; Maldonado, A.; Jiménez, E.; Martín, R.; Rodríguez, J.M. The human milk microbiota: Origin and potential roles in health and disease. Pharmacol. Res. 2013, 69, 1–10. [Google Scholar] [CrossRef]
  58. Gomez-Gallego, C.; Garcia-Mantrana, I.; Salminen, S.; Collado, M.C. The human milk microbiome and factors influencing its composition and activity. Semin. Fetal Neonatal Med. 2016, 21, 400–405. [Google Scholar] [CrossRef]
  59. Collado, M.C.; Rautava, S.; Aakko, J.; Isolauri, E.; Salminen, S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 2016, 6, 23129. [Google Scholar] [CrossRef]
  60. Favier, C.F.; Vaughan, E.E.; Vos, W.M.D.; Akkermans, A.D.L. Molecular Monitoring of Succession of Bacterial Communities in Human Neonates. Appl. Environ. Microbiol. 2002, 68, 219–226. [Google Scholar] [CrossRef]
  61. Macia, L.; Mackay, C.R. Dysfunctional microbiota with reduced capacity to produce butyrate as a basis for allergic diseases. J. Allergy Clin. Immunol. 2019, 144, 1513–1515. [Google Scholar] [CrossRef]
  62. Heikkilä, M.P.; Saris, P.E.J. Inhibition of Staphylococcus aureus by the commensal bacteria of human milk. J. Appl. Microbiol. 2003, 95, 471–478. [Google Scholar] [CrossRef]
  63. Sela, D.A.; Mills, D.A. Nursing our microbiota: Molecular linkages between bifidobacteria and milk oligosaccharides. Trends Microbiol. 2010, 18, 298–307. [Google Scholar] [CrossRef] [PubMed]
  64. Benito, D.; Lozano, C.; Jiménez, E.; Albújar, M.; Gómez, A.; Rodríguez, J.M.; Torres, C. Characterization of Staphylococcus aureus strains isolated from faeces of healthy neonates and potential mother-to-infant microbial transmission through breastfeeding. FEMS Microbiol. Ecol. 2015, 91, fiv007. [Google Scholar] [CrossRef] [PubMed]
  65. Martín, V.; Maldonado-Barragán, A.; Moles, L.; Rodriguez-Baños, M.; Campo, R.d.; Fernández, L.; Rodríguez, J.M.; Jiménez, E. Sharing of Bacterial Strains Between Breast Milk and Infant Feces. J. Hum. Lact. 2012, 28, 36–44. [Google Scholar] [CrossRef]
  66. Prentice, P.M.; Schoemaker, M.H.; Vervoort, J.; Hettinga, K.; Lambers, T.T.; van Tol, E.A.F.; Acerini, C.L.; Olga, L.; Petry, C.J.; Hughes, I.A.; et al. Human Milk Short-Chain Fatty Acid Composition Is Associated with Adiposity Outcomes in Infants. J. Nutr. 2019, 149, 716–722. [Google Scholar] [CrossRef] [PubMed]
  67. Giaquinto, A.N.; Sung, H.; Miller, K.D.; Kramer, J.L.; Newman, L.A.; Minihan, A.; Jemal, A.; Siegel, R.L. Breast Cancer Statistics, 2022. CA Cancer J. Clin. 2022, 72, 524–541. [Google Scholar] [CrossRef]
  68. Bernardo, G.; Le Noci, V.; Di Modica, M.; Montanari, E.; Triulzi, T.; Pupa, S.M.; Tagliabue, E.; Sommariva, M.; Sfondrini, L. The Emerging Role of the Microbiota in Breast Cancer Progression. Cells 2023, 12, 1945. [Google Scholar] [CrossRef]
  69. Kinnel, B.; Singh, S.K.; Oprea-Ilies, G.; Singh, R. Targeted Therapy and Mechanisms of Drug Resistance in Breast Cancer. Cancers 2023, 15, 1320. [Google Scholar] [CrossRef]
  70. Li, J.; Gu, A.; Nong, X.M.; Zhai, S.; Yue, Z.Y.; Li, M.Y.; Liu, Y. Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications. Chem. Rec. 2023, 23, e202300293. [Google Scholar] [CrossRef]
  71. He, T.; Zhao, Z.; Luo, Z.; Jia, W.; Zhang, J.; Zhao, Y.; Xiao, W.; Ming, Z.; Chen, K. Advances in microbial decorations and its applications in drug delivery. Acta Mater. Medica 2023, 2, 466–479. [Google Scholar] [CrossRef]
  72. Liu, J.; Luo, F.; Wen, L.; Zhao, Z.; Sun, H. Current Understanding of Microbiomes in Cancer Metastasis. Cancers 2023, 15, 1893. [Google Scholar] [CrossRef] [PubMed]
  73. Ji, H.; Jiang, Z.; Wei, C.; Ma, Y.; Zhao, J.; Wang, F.; Zhao, B.; Wang, D.; Tang, D. Intratumoural microbiota: From theory to clinical application. Cell Commun. Signal. 2023, 21, 164. [Google Scholar] [CrossRef] [PubMed]
  74. Kim, W.; Kim, E.; Min, H.; Kim, M.G.; Eisenbeis, V.B.; Dutta, A.K.; Pavlovic, I.; Jessen, H.J.; Kim, S.; Seong, R.H. Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase. Proc. Natl. Acad. Sci. USA 2019, 116, 12952–12957. [Google Scholar] [CrossRef]
  75. Weinberg, S.E.; Sun, L.Y.; Yang, A.L.; Liao, J.; Yang, G.Y. Overview of Inositol and Inositol Phosphates on Chemoprevention of Colitis-Induced Carcinogenesis. Molecules 2021, 26, 31. [Google Scholar] [CrossRef] [PubMed]
  76. Marth, J.D.; Grewal, P.K. Mammalian glycosylation in immunity. Nat. Rev. Immunol. 2008, 8, 874–887. [Google Scholar] [CrossRef]
  77. Martínez, Y.; Li, X.; Liu, G.; Bin, P.; Yan, W.; Más, D.; Valdivié, M.; Hu, C.A.; Ren, W.; Yin, Y. The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids 2017, 49, 2091–2098. [Google Scholar] [CrossRef] [PubMed]
  78. Colbert, L.E.; El Alam, M.B.; Wang, R.; Karpinets, T.; Lo, D.; Lynn, E.J.; Harris, T.A.; Elnaggar, J.H.; Yoshida-Court, K.; Tomasic, K.; et al. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring. Cancer Cell 2023, 41, 1945–1962.e11. [Google Scholar] [CrossRef]
  79. Fu, A.; Yao, B.; Dong, T.; Chen, Y.; Yao, J.; Liu, Y.; Li, H.; Bai, H.; Liu, X.; Zhang, Y.; et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell 2022, 185, 1356–1372.e26. [Google Scholar] [CrossRef]
  80. Bullman, S.; Pedamallu, C.S.; Sicinska, E.; Clancy, T.E.; Zhang, X.; Cai, D.; Neuberg, D.; Huang, K.; Guevara, F.; Nelson, T.; et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017, 358, 1443–1448. [Google Scholar] [CrossRef]
  81. Skibinski, A.; Kuperwasser, C. The origin of breast tumor heterogeneity. Oncogene 2015, 34, 5309–5316. [Google Scholar] [CrossRef]
  82. Cappelletti, V.; Iorio, E.; Miodini, P.; Silvestri, M.; Dugo, M.; Daidone, M.G. Metabolic Footprints and Molecular Subtypes in Breast Cancer. Dis. Markers 2017, 2017, 7687851. [Google Scholar] [CrossRef] [PubMed]
  83. Smith, A.; Pierre, J.F.; Makowski, L.; Tolley, E.; Lyn-Cook, B.; Lu, L.; Vidal, G.; Starlard-Davenport, A. Distinct microbial communities that differ by race, stage, or breast-tumor subtype in breast tissues of non-Hispanic Black and non-Hispanic White women. Sci. Rep. 2019, 9, 11940. [Google Scholar] [CrossRef]
  84. Wang, H.; Altemus, J.; Niazi, F.; Green, H.; Calhoun, B.C.; Sturgis, C.; Grobmyer, S.R.; Eng, C. Breast tissue, oral and urinary microbiomes in breast cancer. Oncotarget 2017, 8, 88122–88138. [Google Scholar] [CrossRef]
  85. Hadzega, D.; Minarik, G.; Karaba, M.; Kalavska, K.; Benca, J.; Ciernikova, S.; Sedlackova, T.; Nemcova, P.; Bohac, M.; Pindak, D.; et al. Uncovering Microbial Composition in Human Breast Cancer Primary Tumour Tissue Using Transcriptomic RNA-seq. Int. J. Mol. Sci. 2021, 22, 9058. [Google Scholar] [CrossRef] [PubMed]
  86. Banerjee, S.; Wei, Z.; Tan, F.; Peck, K.N.; Shih, N.; Feldman, M.; Rebbeck, T.R.; Alwine, J.C.; Robertson, E.S. Distinct microbiological signatures associated with triple negative breast cancer. Sci. Rep. 2015, 5, 15162. [Google Scholar] [CrossRef] [PubMed]
  87. Thompson, K.J.; Ingle, J.N.; Tang, X.; Chia, N.; Jeraldo, P.R.; Walther-Antonio, M.R.; Kandimalla, K.K.; Johnson, S.; Yao, J.Z.; Harrington, S.C.; et al. A comprehensive analysis of breast cancer microbiota and host gene expression. PLoS ONE 2017, 12, e0188873. [Google Scholar] [CrossRef]
  88. Chng, K.R.; Chan, S.H.; Ng, A.H.Q.; Li, C.; Jusakul, A.; Bertrand, D.; Wilm, A.; Choo, S.P.; Tan, D.M.Y.; Lim, K.H.; et al. Tissue Microbiome Profiling Identifies an Enrichment of Specific Enteric Bacteria in Opisthorchis viverrini Associated Cholangiocarcinoma. EBioMedicine 2016, 8, 195–202. [Google Scholar] [CrossRef]
  89. Audirac-Chalifour, A.; Torres-Poveda, K.; Bahena-Román, M.; Téllez-Sosa, J.; Martínez-Barnetche, J.; Cortina-Ceballos, B.; López-Estrada, G.; Delgado-Romero, K.; Burguete-García, A.I.; Cantú, D.; et al. Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study. PLoS ONE 2016, 11, e0153274. [Google Scholar] [CrossRef]
  90. Łaniewski, P.; Barnes, D.; Goulder, A.; Cui, H.; Roe, D.J.; Chase, D.M.; Herbst-Kralovetz, M.M. Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. Sci. Rep. 2018, 8, 7593. [Google Scholar] [CrossRef]
  91. Dejea, C.M.; Fathi, P.; Craig, J.M.; Boleij, A.; Taddese, R.; Geis, A.L.; Wu, X.; DeStefano Shields, C.E.; Hechenbleikner, E.M.; Huso, D.L.; et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 2018, 359, 592–597. [Google Scholar] [CrossRef]
  92. Lv, J.; Guo, L.; Liu, J.J.; Zhao, H.P.; Zhang, J.; Wang, J.H. Alteration of the esophageal microbiota in Barrett’s esophagus and esophageal adenocarcinoma. World J. Gastroenterol. 2019, 25, 2149–2161. [Google Scholar] [CrossRef] [PubMed]
  93. Kaakoush, N.O.; Castaño-Rodríguez, N.; Man, S.M.; Mitchell, H.M. Is Campylobacter to esophageal adenocarcinoma as Helicobacter is to gastric adenocarcinoma? Trends Microbiol. 2015, 23, 455–462. [Google Scholar] [CrossRef] [PubMed]
  94. Gao, S.; Li, S.; Ma, Z.; Liang, S.; Shan, T.; Zhang, M.; Zhu, X.; Zhang, P.; Liu, G.; Zhou, F.; et al. Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect. Agent. Cancer 2016, 11, 3. [Google Scholar] [CrossRef] [PubMed]
  95. Avilés-Jiménez, F.; Guitron, A.; Segura-López, F.; Méndez-Tenorio, A.; Iwai, S.; Hernández-Guerrero, A.; Torres, J. Microbiota studies in the bile duct strongly suggest a role for Helicobacter pylori in extrahepatic cholangiocarcinoma. Clin. Microbiol. Infect. 2016, 22, 178.e11–178.e22. [Google Scholar] [CrossRef]
  96. Tsuchiya, Y.; Loza, E.; Villa-Gomez, G.; Trujillo, C.C.; Baez, S.; Asai, T.; Ikoma, T.; Endoh, K.; Nakamura, K. Metagenomics of Microbial Communities in Gallbladder Bile from Patients with Gallbladder Cancer or Cholelithiasis. Asian Pac. J. Cancer Prev. 2018, 19, 961–967. [Google Scholar]
  97. Buti, L.; Spooner, E.; Van der Veen, A.G.; Rappuoli, R.; Covacci, A.; Ploegh, H.L. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc. Natl. Acad. Sci. USA 2011, 108, 9238–9243. [Google Scholar] [CrossRef]
  98. Zhang, S.; Li, C.; Liu, J.; Geng, F.; Shi, X.; Li, Q.; Lu, Z.; Pan, Y. Fusobacterium nucleatum promotes epithelial-mesenchymal transiton through regulation of the lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway. Febs J. 2020, 287, 4032–4047. [Google Scholar] [CrossRef]
  99. Rocha, M.; Avenaud, P.; Ménard, A.; Le Bail, B.; Balabaud, C.; Bioulac-Sage, P.; de Magalhães Queiroz, D.M.; Mégraud, F. Association of Helicobacter species with hepatitis C cirrhosis with or without hepatocellular carcinoma. Gut 2005, 54, 396–401. [Google Scholar] [CrossRef]
  100. Greathouse, K.L.; White, J.R.; Vargas, A.J.; Bliskovsky, V.V.; Beck, J.A.; von Muhlinen, N.; Polley, E.C.; Bowman, E.D.; Khan, M.A.; Robles, A.I.; et al. Interaction between the microbiome and TP53 in human lung cancer. Genome Biol. 2018, 19, 123. [Google Scholar] [CrossRef]
  101. Yu, G.; Gail, M.H.; Consonni, D.; Carugno, M.; Humphrys, M.; Pesatori, A.C.; Caporaso, N.E.; Goedert, J.J.; Ravel, J.; Landi, M.T. Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features. Genome Biol. 2016, 17, 163. [Google Scholar] [CrossRef]
  102. Schmidt, B.L.; Kuczynski, J.; Bhattacharya, A.; Huey, B.; Corby, P.M.; Queiroz, E.L.; Nightingale, K.; Kerr, A.R.; DeLacure, M.D.; Veeramachaneni, R.; et al. Changes in abundance of oral microbiota associated with oral cancer. PLoS ONE 2014, 9, e98741. [Google Scholar] [CrossRef] [PubMed]
  103. Chan, P.J.; Seraj, I.M.; Kalugdan, T.H.; King, A. Prevalence of mycoplasma conserved DNA in malignant ovarian cancer detected using sensitive PCR-ELISA. Gynecol. Oncol. 1996, 63, 258–260. [Google Scholar] [CrossRef] [PubMed]
  104. Geller, L.T.; Barzily-Rokni, M.; Danino, T.; Jonas, O.H.; Shental, N.; Nejman, D.; Gavert, N.; Zwang, Y.; Cooper, Z.A.; Shee, K.; et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017, 357, 1156–1160. [Google Scholar] [CrossRef] [PubMed]
  105. Pushalkar, S.; Hundeyin, M.; Daley, D.; Zambirinis, C.P.; Kurz, E.; Mishra, A.; Mohan, N.; Aykut, B.; Usyk, M.; Torres, L.E.; et al. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Cancer Discov. 2018, 8, 403–416. [Google Scholar] [CrossRef]
  106. Aykut, B.; Pushalkar, S.; Chen, R.; Li, Q.; Abengozar, R.; Kim, J.I.; Shadaloey, S.A.; Wu, D.; Preiss, P.; Verma, N.; et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 2019, 574, 264–267. [Google Scholar] [CrossRef]
  107. Cavarretta, I.; Ferrarese, R.; Cazzaniga, W.; Saita, D.; Lucianò, R.; Ceresola, E.R.; Locatelli, I.; Visconti, L.; Lavorgna, G.; Briganti, A.; et al. The Microbiome of the Prostate Tumor Microenvironment. Eur. Urol. 2017, 72, 625–631. [Google Scholar] [CrossRef]
  108. Cohen, R.J.; Shannon, B.A.; McNeal, J.E.; Shannon, T.; Garrett, K.L. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: A possible link to cancer evolution? J. Urol. 2005, 173, 1969–1974. [Google Scholar] [CrossRef] [PubMed]
  109. Liu, Y.; Baba, Y.; Ishimoto, T.; Tsutsuki, H.; Zhang, T.; Nomoto, D.; Okadome, K.; Yamamura, K.; Harada, K.; Eto, K.; et al. Fusobacterium nucleatum confers chemoresistance by modulating autophagy in oesophageal squamous cell carcinoma. Br. J. Cancer 2021, 124, 963–974. [Google Scholar] [CrossRef]
  110. Xuan, C.; Shamonki, J.M.; Chung, A.; Dinome, M.L.; Chung, M.; Sieling, P.A.; Lee, D.J. Microbial dysbiosis is associated with human breast cancer. PLoS ONE 2014, 9, e83744. [Google Scholar] [CrossRef]
  111. Parida, S.; Siddharth, S.; Xia, Y.; Sharma, D. Concomitant analyses of intratumoral microbiota and genomic features reveal distinct racial differences in breast cancer. npj Breast Cancer 2023, 9, 4. [Google Scholar] [CrossRef]
  112. Thyagarajan, S.; Zhang, Y.; Thapa, S.; Allen, M.S.; Phillips, N.; Chaudhary, P.; Kashyap, M.V.; Vishwanatha, J.K. Comparative analysis of racial differences in breast tumor microbiome. Sci. Rep. 2020, 10, 14116. [Google Scholar] [CrossRef] [PubMed]
  113. Dalmasso, G.; Nguyen, H.T.; Yan, Y.; Laroui, H.; Charania, M.A.; Ayyadurai, S.; Sitaraman, S.V.; Merlin, D. Microbiota modulate host gene expression via microRNAs. PLoS ONE 2011, 6, e19293. [Google Scholar] [CrossRef] [PubMed]
  114. Mody, D.; Verma, V.; Rani, V. Modulating host gene expression via gut microbiome-microRNA interplay to treat human diseases. Crit. Rev. Microbiol. 2021, 47, 596–611. [Google Scholar] [CrossRef] [PubMed]
  115. Yuan, Y.; Leeds, J.A.; Meredith, T.C. Pseudomonas aeruginosa directly shunts β-oxidation degradation intermediates into de novo fatty acid biosynthesis. J. Bacteriol. 2012, 194, 5185–5196. [Google Scholar] [CrossRef]
  116. Park, S.M.; Choi, W.S.; Yoon, Y.; Jung, G.H.; Lee, C.K.; Ahn, S.H.; Wonsuck, Y.; Yoo, Y. Breast abscess caused by Staphylococcus aureus in 2 adolescent girls with atopic dermatitis. Korean J. Pediatr. 2018, 61, 200–204. [Google Scholar] [CrossRef] [PubMed]
  117. Chiba, A.; Bawaneh, A.; Velazquez, C.; Clear, K.Y.J.; Wilson, A.S.; Howard-McNatt, M.; Levine, E.A.; Levi-Polyachenko, N.; Yates-Alston, S.A.; Diggle, S.P.; et al. Neoadjuvant Chemotherapy Shifts Breast Tumor Microbiota Populations to Regulate Drug Responsiveness and the Development of Metastasis. Mol. Cancer Res. 2020, 18, 130–139. [Google Scholar] [CrossRef]
  118. Gotland, N.; Uhre, M.L.; Sandholdt, H.; Mejer, N.; Lundbo, L.F.; Petersen, A.; Larsen, A.R.; Benfield, T. Increased risk of incident primary cancer after Staphylococcus aureus bacteremia: A matched cohort study. Medicine 2020, 99, e19984. [Google Scholar] [CrossRef]
  119. Kullander, J.; Forslund, O.; Dillner, J. Staphylococcus aureus and squamous cell carcinoma of the skin. Cancer Epidemiol. Biomark. Prev. 2009, 18, 472–478. [Google Scholar] [CrossRef]
  120. Grice, E.A.; Segre, J.A. The skin microbiome. Nat. Rev. Microbiol. 2011, 9, 244–253. [Google Scholar] [CrossRef]
  121. Yu, H.-j.; Deng, H.; Ma, J.; Huang, S.-j.; Yang, J.-m.; Huang, Y.-f.; Mu, X.-p.; Zhang, L.; Wang, Q. Clinical metagenomic analysis of bacterial communities in breast abscesses of granulomatous mastitis. Int. J. Infect. Dis. 2016, 53, 30–33. [Google Scholar] [CrossRef]
  122. Bi, J.; Li, Z.; Lin, X.; Li, F.; Xu, H.; Yu, X.; Liu, L.; Liang, Y.; Xu, Z.; Wang, J.; et al. Etiology of granulomatous lobular mastitis based on metagenomic next-generation sequencing. Int. J. Infect. Dis. 2021, 113, 243–250. [Google Scholar] [CrossRef]
  123. Carvajal, J.; Carvajal, M.; Hernández, G. Back to Basics: Could the Preoperative Skin Antiseptic Agent Help Prevent Biofilm-Related Capsular Contracture? Aesthet. Surg. J. 2019, 39, 848–859. [Google Scholar] [CrossRef] [PubMed]
  124. Bachour, Y.; Poort, L.; Verweij, S.P.; van Selms, G.; Winters, H.A.H.; Ritt, M.J.P.F.; Niessen, F.B.; Budding, A.E. PCR Characterization of Microbiota on Contracted and Non-Contracted Breast Capsules. Aesthetic Plast. Surg. 2019, 43, 918–926. [Google Scholar] [CrossRef]
  125. Rieger, U.M.; Mesina, J.; Kalbermatten, D.F.; Haug, M.; Frey, H.P.; Pico, R.; Frei, R.; Pierer, G.; Lüscher, N.J.; Trampuz, A. Bacterial biofilms and capsular contracture in patients with breast implants. Br. J. Surg. 2013, 100, 768–774. [Google Scholar] [CrossRef] [PubMed]
  126. Hu, H.; Johani, K.; Almatroudi, A.; Vickery, K.; Van Natta, B.; Kadin, M.E.; Brody, G.; Clemens, M.; Cheah, C.Y.; Lade, S.; et al. Bacterial Biofilm Infection Detected in Breast Implant–Associated Anaplastic Large-Cell Lymphoma. Plast. Reconstr. Surg. 2016, 137, 1659–1669. [Google Scholar] [CrossRef]
  127. Walker, J.N.; Hanson, B.M.; Pinkner, C.L.; Simar, S.R.; Pinkner, J.S.; Parikh, R.; Clemens, M.W.; Hultgren, S.J.; Myckatyn, T.M. Insights into the Microbiome of Breast Implants and Periprosthetic Tissue in Breast Implant-Associated Anaplastic Large Cell Lymphoma. Sci. Rep. 2019, 9, 10393. [Google Scholar] [CrossRef] [PubMed]
  128. Love, S.M.; Barsky, S.H. Anatomy of the nipple and breast ducts revisited. Cancer 2004, 101, 1947–1957. [Google Scholar] [CrossRef]
  129. West, P.A.; Hewitt, J.H.; Murphy, O.M. Influence of methods of collection and storage on the bacteriology of human milk. J. Appl. Bacteriol. 1979, 46, 269–277. [Google Scholar] [CrossRef]
  130. Chan, A.A.; Bashir, M.; Rivas, M.N.; Duvall, K.; Sieling, P.A.; Pieber, T.R.; Vaishampayan, P.A.; Love, S.M.; Lee, D.J. Characterization of the microbiome of nipple aspirate fluid of breast cancer survivors. Sci. Rep. 2016, 6, 28061. [Google Scholar] [CrossRef]
  131. Ramsay, D.T.; Kent, J.C.; Owens, R.A.; Hartmann, P.E. Ultrasound Imaging of Milk Ejection in the Breast of Lactating Women. Pediatrics 2004, 113, 361–367. [Google Scholar] [CrossRef]
  132. Berg, R.D. Bacterial translocation from the gastrointestinal tract. Adv. Exp. Med. Biol. 1999, 473, 11–30. [Google Scholar] [CrossRef]
  133. Sedman, P.C.; Macfie, J.; Sagar, P.; Mitchell, C.J.; May, J.; Mancey-Jones, B.; Johnstone, D. The prevalence of gut translocation in humans. Gastroenterology 1994, 107, 643–649. [Google Scholar] [CrossRef] [PubMed]
  134. Rodriguez, A.V.; Baigorí, M.D.; Alvarez, S.; Castro, G.R.; Oliver, G. Phosphatidylinositol-specific phospholipase C activity in Lactobacillus rhamnosus with capacity to translocate. FEMS Microbiol. Lett. 2001, 204, 33–38. [Google Scholar] [CrossRef] [PubMed]
  135. Berg, R.D. Bacterial translocation from the gastrointestinal tract. Trends Microbiol. 1995, 3, 149–154. [Google Scholar] [CrossRef] [PubMed]
  136. Perez, P.F.; Doré, J.l.; Leclerc, M.; Levenez, F.; Benyacoub, J.; Serrant, P.; Segura-Roggero, I.; Schiffrin, E.J.; Donnet-Hughes, A. Bacterial Imprinting of the Neonatal Immune System: Lessons From Maternal Cells? Pediatrics 2007, 119, e724–e732. [Google Scholar] [CrossRef]
  137. Cronin, M.; Morrissey, D.; Rajendran, S.; El Mashad, S.M.; van Sinderen, D.; O’Sullivan, G.C.; Tangney, M. Orally administered bifidobacteria as vehicles for delivery of agents to systemic tumors. Mol. Ther. 2010, 18, 1397–1407. [Google Scholar] [CrossRef]
  138. Danino, T.; Prindle, A.; Kwong, G.A.; Skalak, M.; Li, H.; Allen, K.; Hasty, J.; Bhatia, S.N. Programmable probiotics for detection of cancer in urine. Sci. Transl. Med. 2015, 7, 289ra284. [Google Scholar] [CrossRef]
  139. Mira, A.; Rodríguez, J. Prebiotics and Probiotics in Human Milk; Academic Press: Cambridge, MA, USA, 2017. [Google Scholar]
  140. Brandtzaeg, P. The mucosal immune system and its integration with the mammary glands. J. Pediatr. 2010, 156, S8–S15. [Google Scholar] [CrossRef]
  141. Goldman, A.S.; Goldblum, R.M. Transfer of maternal leukocytes to the infant by human milk. Curr. Top. Microbiol. Immunol. 1997, 222, 205–213. [Google Scholar]
  142. Trend, S.; de Jong, E.; Lloyd, M.L.; Kok, C.H.; Richmond, P.; Doherty, D.A.; Simmer, K.; Kakulas, F.; Strunk, T.; Currie, A. Leukocyte Populations in Human Preterm and Term Breast Milk Identified by Multicolour Flow Cytometry. PLoS ONE 2015, 10, e0135580. [Google Scholar] [CrossRef]
  143. Tuaillon, E.; Valea, D.; Becquart, P.; Al Tabaa, Y.; Meda, N.; Bollore, K.; Van de Perre, P.; Vendrell, J.P. Human milk-derived B cells: A highly activated switched memory cell population primed to secrete antibodies. J. Immunol. 2009, 182, 7155–7162. [Google Scholar] [CrossRef]
  144. Cabinian, A.; Sinsimer, D.; Tang, M.; Zumba, O.; Mehta, H.; Toma, A.; Sant’Angelo, D.; Laouar, Y.; Laouar, A. Transfer of Maternal Immune Cells by Breastfeeding: Maternal Cytotoxic T Lymphocytes Present in Breast Milk Localize in the Peyer’s Patches of the Nursed Infant. PLoS ONE 2016, 11, e0156762. [Google Scholar] [CrossRef] [PubMed]
  145. Hammond, K.A. Adaptation of the maternal intestine during lactation. J. Mammary Gland. Biol. Neoplasia 1997, 2, 243–252. [Google Scholar] [CrossRef]
  146. Gosalbes, M.J.; Compte, J.; Moriano-Gutierrez, S.; Vallès, Y.; Jiménez-Hernández, N.; Pons, X.; Artacho, A.; Francino, M.P. Metabolic adaptation in the human gut microbiota during pregnancy and the first year of life. EBioMedicine 2019, 39, 497–509. [Google Scholar] [CrossRef] [PubMed]
  147. Jiménez, E.; Fernández, L.; Maldonado, A.; Martín, R.; Olivares, M.; Xaus, J.; Rodríguez, J.M. Oral Administration of Lactobacillus Strains Isolated from Breast Milk as an Alternative for the Treatment of Infectious Mastitis during Lactation. Appl. Environ. Microbiol. 2008, 74, 4650–4655. [Google Scholar] [CrossRef] [PubMed]
  148. Arroyo, R.; Martín, V.; Maldonado, A.; Jiménez, E.; Fernández, L.; Rodríguez, J.M. Treatment of Infectious Mastitis during Lactation: Antibiotics versus Oral Administration of Lactobacilli Isolated from Breast Milk. Clin. Infect. Dis. 2010, 50, 1551–1558. [Google Scholar] [CrossRef] [PubMed]
  149. Moossavi, S.; Azad, M.B. Origins of human milk microbiota: New evidence and arising questions. Gut Microbes 2020, 12, 1667722. [Google Scholar] [CrossRef]
  150. Li, S.; He, M.; Lei, Y.; Liu, Y.; Li, X.; Xiang, X.; Wu, Q.; Wang, Q. Oral Microbiota and Tumor-A New Perspective of Tumor Pathogenesis. Microorganisms 2022, 10. [Google Scholar] [CrossRef]
  151. Petris, C.K.; Golomb, M.; Phillips, T.E. Bacterial Transcytosis across Conjunctival M Cells. Investig. Ophthalmol. Vis. Sci. 2007, 48, 2172–2177. [Google Scholar] [CrossRef]
  152. Neal, M.D.; Leaphart, C.; Levy, R.; Prince, J.; Billiar, T.R.; Watkins, S.; Li, J.; Cetin, S.; Ford, H.; Schreiber, A.; et al. Enterocyte TLR4 mediates phagocytosis and translocation of bacteria across the intestinal barrier. J. Immunol. 2006, 176, 3070–3079. [Google Scholar] [CrossRef]
  153. Wang, G.; Moniri, N.H.; Ozawa, K.; Stamler, J.S.; Daaka, Y. Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc. Natl. Acad. Sci. USA 2006, 103, 1295–1300. [Google Scholar] [CrossRef] [PubMed]
  154. Wells, C.L.; VandeWesterlo, E.M.; Jechorek, R.P.; Erlandsen, S.L. Effect of hypoxia on enterocyte endocytosis of enteric bacteria. Crit. Care Med. 1996, 24, 985–991. [Google Scholar] [CrossRef] [PubMed]
  155. Wang, A.; Keita, Å.V.; Phan, V.; McKay, C.M.; Schoultz, I.; Lee, J.; Murphy, M.P.; Fernando, M.; Ronaghan, N.; Balce, D.; et al. Targeting mitochondria-derived reactive oxygen species to reduce epithelial barrier dysfunction and colitis. Am. J. Pathol. 2014, 184, 2516–2527. [Google Scholar] [CrossRef] [PubMed]
  156. Lewis, K.; Lutgendorff, F.; Phan, V.; Söderholm, J.D.; Sherman, P.M.; McKay, D.M. Enhanced translocation of bacteria across metabolically stressed epithelia is reduced by butyrate. Inflamm. Bowel Dis. 2010, 16, 1138–1148. [Google Scholar] [CrossRef]
  157. Clark, E.; Hoare, C.; Tanianis-Hughes, J.; Carlson, G.L.; Warhurst, G. Interferon gamma induces translocation of commensal Escherichia coli across gut epithelial cells via a lipid raft-mediated process. Gastroenterology 2005, 128, 1258–1267. [Google Scholar] [CrossRef]
  158. Smyth, D.; McKay, C.M.; Gulbransen, B.D.; Phan, V.C.; Wang, A.; McKay, D.M. Interferon-gamma signals via an ERK1/2-ARF6 pathway to promote bacterial internalization by gut epithelia. Cell Microbiol. 2012, 14, 1257–1270. [Google Scholar] [CrossRef]
  159. Chen, T.L.; Chen, S.; Wu, H.W.; Lee, T.C.; Lu, Y.Z.; Wu, L.L.; Ni, Y.H.; Sun, C.H.; Yu, W.H.; Buret, A.G.; et al. Persistent gut barrier damage and commensal bacterial influx following eradication of Giardia infection in mice. Gut Pathog. 2013, 5, 26. [Google Scholar] [CrossRef] [PubMed]
  160. Kalischuk, L.D.; Inglis, G.D.; Buret, A.G. Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts. Gut Pathog. 2009, 1, 2. [Google Scholar] [CrossRef]
  161. Wu, L.L.; Peng, W.H.; Kuo, W.T.; Huang, C.Y.; Ni, Y.H.; Lu, K.S.; Turner, J.R.; Yu, L.C. Commensal bacterial endocytosis in epithelial cells is dependent on myosin light chain kinase-activated brush border fanning by interferon-γ. Am. J. Pathol. 2014, 184, 2260–2274. [Google Scholar] [CrossRef]
  162. Tosi, T.; Pflug, A.; Discola, K.F.; Neves, D.; Dessen, A. Structural basis of eukaryotic cell targeting by type III secretion system (T3SS) effectors. Res. Microbiol. 2013, 164, 605–619. [Google Scholar] [CrossRef]
  163. Rescigno, M.; Urbano, M.; Valzasina, B.; Francolini, M.; Rotta, G.; Bonasio, R.; Granucci, F.; Kraehenbuhl, J.-P.; Ricciardi-Castagnoli, P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2001, 2, 361–367. [Google Scholar] [CrossRef] [PubMed]
  164. Vazquez-Torres, A.; Jones-Carson, J.; Bäumler, A.J.; Falkow, S.; Valdivia, R.; Brown, W.; Le, M.; Berggren, R.; Parks, W.T.; Fang, F.C. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 1999, 401, 804–808. [Google Scholar] [CrossRef]
  165. Langa, S. Interactions between Lactic Acid Bacteria, Intestinal Epithelial Cells and Immune Cells. Development of In Vitro Models; Complutense University of Madrid: Madrid, Spain, 2006. [Google Scholar]
  166. Langa, S.; Maldonado-Barragán, A.; Delgado, S.; Martín, R.; Martín, V.; Jiménez, E.; Ruíz-Barba, J.L.; Mayo, B.; Connor, R.I.; Suárez, J.E.; et al. Characterization of Lactobacillus salivarius CECT 5713, a strain isolated from human milk: From genotype to phenotype. Appl. Microbiol. Biotechnol. 2012, 94, 1279–1287. [Google Scholar] [CrossRef]
  167. Rescigno, M.; Citterio, S.; Thèry, C.; Rittig, M.; Medaglini, D.; Pozzi, G.; Amigorena, S.; Ricciardi-Castagnoli, P. Bacteria-induced neo-biosynthesis, stabilization, and surface expression of functional class I molecules in mouse dendritic cells. Proc. Natl. Acad. Sci. USA 1998, 95, 5229–5234. [Google Scholar] [CrossRef]
  168. Macpherson, A.J.; Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 2004, 303, 1662–1665. [Google Scholar] [CrossRef] [PubMed]
  169. Fung, T.C.; Bessman, N.J.; Hepworth, M.R.; Kumar, N.; Shibata, N.; Kobuley, D.; Wang, K.; Ziegler, C.G.K.; Goc, J.; Shima, T.; et al. Lymphoid-Tissue-Resident Commensal Bacteria Promote Members of the IL-10 Cytokine Family to Establish Mutualism. Immunity 2016, 44, 634–646. [Google Scholar] [CrossRef] [PubMed]
  170. Roitt, I.M. Essential Immunology; Blackwell Scientific: Oxford, UK, 1974. [Google Scholar]
  171. Martín, R.o.; Langa, S.; Reviriego, C.; Jiménez, E.; Marín, M.a.L.; Olivares, M.; Boza, J.; Jiménez, J.; Fernández, L.; Xaus, J. The commensal microflora of human milk: New perspectives for food bacteriotherapy and probiotics. Trends Food Sci. Technol. 2004, 15, 121–127. [Google Scholar] [CrossRef]
  172. Bertotto, A.; Gerli, R.; Castellucci, G.; Scalise, F.; Vaccaro, R. Human milk lymphocytes bearing the gamma/delta T-cell receptor are mostly delta TCS1-positive cells. Immunology 1991, 74, 360. [Google Scholar]
  173. Zheng, Y.; Corrêa-Silva, S.; de Souza, E.C.; Maria Rodrigues, R.; da Fonseca, F.A.M.; Gilio, A.E.; Carneiro-Sampaio, M.; Palmeira, P. Macrophage profile and homing into breast milk in response to ongoing respiratory infections in the nursing infant. Cytokine 2020, 129, 155045. [Google Scholar] [CrossRef]
  174. Lluch, J.; Servant, F.; Païssé, S.; Valle, C.; Valiere, S.; Kuchly, C.; Vilchez, G.; Donnadieu, C.; Courtney, M.; Burcelin, R. The characterization of novel tissue microbiota using an optimized 16S metagenomic sequencing pipeline. PLoS ONE 2015, 10, e0142334. [Google Scholar] [CrossRef]
  175. Dunn, C.M.; Velasco, C.; Rivas, A.; Andrews, M.; Garman, C.; Jacob, P.B.; Jeffries, M.A. Identification of cartilage microbial DNA signatures and associations with knee and hip osteoarthritis. Arthritis Rheumatol. 2020, 72, 1111–1122. [Google Scholar] [CrossRef] [PubMed]
  176. Berthelot, J.-M.; Lioté, F.; Sibilia, J. Tissue microbiota: A ‘secondary-self’, first target of autoimmunity? Jt. Bone Spine 2022, 89, 105337. [Google Scholar] [CrossRef] [PubMed]
  177. Hosang, L.; Canals, R.C.; van der Flier, F.J.; Hollensteiner, J.; Daniel, R.; Flügel, A.; Odoardi, F. The lung microbiome regulates brain autoimmunity. Nature 2022, 603, 138–144. [Google Scholar] [CrossRef]
  178. Mak, T.W.; Saunders, M.E.; Jett, B.D. Immunity to Infection. In Primer to the Immune Response; Newnes: Oxford, UK, 2014; pp. 295–332. [Google Scholar]
  179. Cullin, N.; Antunes, C.A.; Straussman, R.; Stein-Thoeringer, C.K.; Elinav, E. Microbiome and cancer. Cancer Cell 2021, 39, 1317–1341. [Google Scholar] [CrossRef]
  180. WHO; IARC. IARC monographs program on the evaluation of carcinogenic risks to humans-some industrial-chemicals, Lyon, 15-22 February 1994-preamble. IARC Monogr. Eval. Carcinog. Risks Hum. 1994, 60, 13–33. [Google Scholar]
  181. Kovács, T.; Mikó, E.; Vida, A.; Sebő, É.; Toth, J.; Csonka, T.; Boratkó, A.; Ujlaki, G.; Lente, G.; Kovács, P.; et al. Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors. Sci. Rep. 2019, 9, 1300. [Google Scholar] [CrossRef] [PubMed]
  182. Sári, Z.; Mikó, E.; Kovács, T.; Jankó, L.; Csonka, T.; Lente, G.; Sebő, É.; Tóth, J.; Tóth, D.; Árkosy, P.; et al. Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress. Cancers 2020, 12, 2411. [Google Scholar] [CrossRef]
  183. Zhang, J.; Lu, R.; Zhang, Y.; Matuszek, Ż.; Zhang, W.; Xia, Y.; Pan, T.; Sun, J. tRNA Queuosine Modification Enzyme Modulates the Growth and Microbiome Recruitment to Breast Tumors. Cancers 2020, 12, 628. [Google Scholar] [CrossRef] [PubMed]
  184. Yuan, Y.; Zallot, R.; Grove, T.L.; Payan, D.J.; Martin-Verstraete, I.; Šepić, S.; Balamkundu, S.; Neelakandan, R.; Gadi, V.K.; Liu, C.F.; et al. Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens. Proc. Natl. Acad. Sci. USA 2019, 116, 19126–19135. [Google Scholar] [CrossRef]
  185. Hoyles, L.; Jiménez-Pranteda, M.L.; Chilloux, J.; Brial, F.; Myridakis, A.; Aranias, T.; Magnan, C.; Gibson, G.R.; Sanderson, J.D.; Nicholson, J.K.; et al. Metabolic retroconversion of trimethylamine N-oxide and the gut microbiota. Microbiome 2018, 6, 73. [Google Scholar] [CrossRef]
  186. Liang, Y.; Li, Q.; Liu, Y.; Guo, Y.; Li, Q. Awareness of intratumoral bacteria and their potential application in cancer treatment. Discov. Oncol. 2023, 14, 57. [Google Scholar] [CrossRef] [PubMed]
  187. Viswanathan, S.; Parida, S.; Lingipilli, B.T.; Krishnan, R.; Podipireddy, D.R.; Muniraj, N. Role of Gut Microbiota in Breast Cancer and Drug Resistance. Pathogens 2023, 12, 468. [Google Scholar] [CrossRef] [PubMed]
  188. Feng, K.; Ren, F.; Shang, Q.; Wang, X.; Wang, X. Association between oral microbiome and breast cancer in the east Asian population: A Mendelian randomization and case–control study. Thorac. Cancer 2024, 15, 974–986. [Google Scholar] [CrossRef] [PubMed]
  189. Kostic, A.D.; Chun, E.; Robertson, L.; Glickman, J.N.; Gallini, C.A.; Michaud, M.; Clancy, T.E.; Chung, D.C.; Lochhead, P.; Hold, G.L.; et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 2013, 14, 207–215. [Google Scholar] [CrossRef] [PubMed]
  190. Groeger, S.; Zhou, Y.; Ruf, S.; Meyle, J. Pathogenic Mechanisms of Fusobacterium nucleatum on Oral Epithelial Cells. Front. Oral Health 2022, 3, 831607. [Google Scholar] [CrossRef]
  191. Castellarin, M.; Warren, R.L.; Freeman, J.D.; Dreolini, L.; Krzywinski, M.; Strauss, J.; Barnes, R.; Watson, P.; Allen-Vercoe, E.; Moore, R.A.; et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012, 22, 299–306. [Google Scholar] [CrossRef]
  192. Xu, M.; Yamada, M.; Li, M.; Liu, H.; Chen, S.G.; Han, Y.W. FadA from Fusobacterium nucleatum Utilizes both Secreted and Nonsecreted Forms for Functional Oligomerization for Attachment and Invasion of Host Cells*. J. Biol. Chem. 2007, 282, 25000–25009. [Google Scholar] [CrossRef]
  193. Meng, Q.; Gao, Q.; Mehrazarin, S.; Tangwanichgapong, K.; Wang, Y.; Huang, Y.; Pan, Y.; Robinson, S.; Liu, Z.; Zangiabadi, A.; et al. Fusobacterium nucleatum secretes amyloid-like FadA to enhance pathogenicity. EMBO Rep. 2021, 22, e52891. [Google Scholar] [CrossRef]
  194. Han, Y.W.; Redline, R.W.; Li, M.; Yin, L.; Hill, G.B.; McCormick, T.S. Fusobacterium nucleatum Induces Premature and Term Stillbirths in Pregnant Mice: Implication of Oral Bacteria in Preterm Birth. Infect. Immun. 2004, 72, 2272–2279. [Google Scholar] [CrossRef]
  195. Han, Y.W.; Shi, W.; Huang, G.T.J.; Kinder Haake, S.; Park, N.H.; Kuramitsu, H.; Genco, R.J. Interactions between periodontal bacteria and human oral epithelial cells: Fusobacterium nucleatum adheres to and invades epithelial cells. Infect. Immun. 2000, 68, 3140–3146. [Google Scholar] [CrossRef]
  196. Engevik, M.A.; Danhof, H.A.; Ruan, W.; Engevik, A.C.; Chang-Graham, A.L.; Engevik, K.A.; Shi, Z.; Zhao, Y.; Brand, C.K.; Krystofiak, E.S. Fusobacterium nucleatum secretes outer membrane vesicles and promotes intestinal inflammation. MBio 2021, 12, 10.1128. [Google Scholar] [CrossRef]
  197. Nagata, E.; Oho, T. Invasive Streptococcus mutans induces inflammatory cytokine production in human aortic endothelial cells via regulation of intracellular toll-like receptor 2 and nucleotide-binding oligomerization domain 2. Mol. Oral Microbiol. 2017, 32, 131–141. [Google Scholar] [CrossRef]
  198. Yu, L.; Maishi, N.; Akahori, E.; Hasebe, A.; Takeda, R.; Matsuda, A.Y.; Hida, Y.; Nam, J.-M.; Onodera, Y.; Kitagawa, Y.; et al. The oral bacterium Streptococcus mutans promotes tumor metastasis by inducing vascular inflammation. Cancer Sci. 2022, 113, 3980–3994. [Google Scholar] [CrossRef]
  199. Vela, A.I.; Rey, V.S.d.; Zamora, L.; Casamayor, A.; Domínguez, L.; Fernández-Garayzábal, J.F. Streptococcus cuniculi sp. nov., isolated from the respiratory tract of wild rabbits. Int. J. Syst. Evol. Microbiol. 2014, 64 Pt 7, 2486–2490. [Google Scholar] [CrossRef] [PubMed]
  200. Li, N.; Zhou, H.; Holden, V.K.; Deepak, J.; Dhilipkannah, P.; Todd, N.W.; Stass, S.A.; Jiang, F. Streptococcus pneumoniae promotes lung cancer development and progression. iScience 2023, 26, 105923. [Google Scholar] [CrossRef] [PubMed]
  201. Liu, B.; Huang, J.; Xiao, J.; Xu, W.; Zhang, H.; Yuan, Y.; Yin, Y.; Zhang, X. The Streptococcus virulence protein PepO triggers anti-tumor immune responses by reprograming tumor-associated macrophages in a mouse triple negative breast cancer model. Cell Biosci. 2023, 13, 198. [Google Scholar] [CrossRef] [PubMed]
  202. Ma, J.; Gnanasekar, A.; Lee, A.; Li, W.T.; Haas, M.; Wang-Rodriguez, J.; Chang, E.Y.; Rajasekaran, M.; Ongkeko, W.M. Influence of Intratumor Microbiome on Clinical Outcome and Immune Processes in Prostate Cancer. Cancers 2020, 12, 2524. [Google Scholar] [CrossRef]
  203. Henao-Martínez, A.F.; González-Fontal, G.R.; Castillo-Mancilla, J.R.; Yang, I.V. Enterobacteriaceae bacteremias among cancer patients: An observational cohort study. Int. J. Infect. Dis. 2013, 17, e374–e378. [Google Scholar] [CrossRef]
  204. Oliero, M.; Calvé, A.; Fragoso, G.; Cuisiniere, T.; Hajjar, R.; Dobrindt, U.; Santos, M.M. Oligosaccharides increase the genotoxic effect of colibactin produced by pks+ Escherichia coli strains. BMC Cancer 2021, 21, 172. [Google Scholar] [CrossRef]
  205. Aschtgen, M.-S.; Fragkoulis, K.; Sanz, G.; Normark, S.; Selivanova, G.; Henriques-Normark, B.; Peuget, S. Enterobacteria impair host p53 tumor suppressor activity through mRNA destabilization. Oncogene 2022, 41, 2173–2186. [Google Scholar] [CrossRef]
  206. Giallourou, N.; Urbaniak, C.; Puebla-Barragan, S.; Vorkas, P.A.; Swann, J.R.; Reid, G. Characterizing the breast cancer lipidome and its interaction with the tissue microbiota. Commun. Biol. 2021, 4, 1229. [Google Scholar] [CrossRef]
  207. Liu, P.; Zhu, W.; Chen, C.; Yan, B.; Zhu, L.; Chen, X.; Peng, C. The mechanisms of lysophosphatidylcholine in the development of diseases. Life Sci. 2020, 247, 117443. [Google Scholar] [CrossRef] [PubMed]
  208. Parkin, D.M. The global health burden of infection-associated cancers in the year 2002. Int. J. Cancer 2006, 118, 3030–3044. [Google Scholar] [CrossRef] [PubMed]
  209. Cao, Y.; Xia, H.; Tan, X.; Shi, C.; Ma, Y.; Meng, D.; Zhou, M.; Lv, Z.; Wang, S.; Jin, Y. Intratumoural microbiota: A new frontier in cancer development and therapy. Signal Transduct. Target. Ther. 2024, 9, 15. [Google Scholar] [CrossRef]
  210. Lawson, J.S.; Heng, B. Viruses and breast cancer. Cancers 2010, 2, 752–772. [Google Scholar] [CrossRef]
  211. Lau, L.; Gray, E.E.; Brunette, R.L.; Stetson, D.B. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 2015, 350, 568–571. [Google Scholar] [CrossRef]
  212. Luo, X.; Donnelly, C.R.; Gong, W.; Heath, B.R.; Hao, Y.; Donnelly, L.A.; Moghbeli, T.; Tan, Y.S.; Lin, X.; Bellile, E.; et al. HPV16 drives cancer immune escape via NLRX1-mediated degradation of STING. J. Clin. Investig. 2020, 130, 1635–1652. [Google Scholar] [CrossRef] [PubMed]
  213. Wang, L.W.; Jiang, S.; Gewurz, B.E. Epstein-Barr Virus LMP1-Mediated Oncogenicity. J. Virol. 2017, 91. [Google Scholar] [CrossRef]
  214. Floor, S.L.; Dumont, J.E.; Maenhaut, C.; Raspe, E. Hallmarks of cancer: Of all cancer cells, all the time? Trends Mol. Med. 2012, 18, 509–515. [Google Scholar] [CrossRef]
  215. Santos, J.C.; Brianti, M.T.; Almeida, V.R.; Ortega, M.M.; Fischer, W.; Haas, R.; Matheu, A.; Ribeiro, M.L. Helicobacter pylori infection modulates the expression of miRNAs associated with DNA mismatch repair pathway. Mol. Carcinog. 2017, 56, 1372–1379. [Google Scholar] [CrossRef]
  216. Goodwin, A.C.; Destefano Shields, C.E.; Wu, S.; Huso, D.L.; Wu, X.; Murray-Stewart, T.R.; Hacker-Prietz, A.; Rabizadeh, S.; Woster, P.M.; Sears, C.L.; et al. Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis. Proc. Natl. Acad. Sci. USA 2011, 108, 15354–15359. [Google Scholar] [CrossRef]
  217. Guo, P.; Tian, Z.; Kong, X.; Yang, L.; Shan, X.; Dong, B.; Ding, X.; Jing, X.; Jiang, C.; Jiang, N.; et al. FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2. J. Exp. Clin. Cancer Res. 2020, 39, 202. [Google Scholar] [CrossRef]
  218. Geng, F.; Zhang, Y.; Lu, Z.; Zhang, S.; Pan, Y. Fusobacterium nucleatum Caused DNA Damage and Promoted Cell Proliferation by the Ku70/p53 Pathway in Oral Cancer Cells. DNA Cell Biol. 2020, 39, 144–151. [Google Scholar] [CrossRef] [PubMed]
  219. Maddocks, O.D.; Scanlon, K.M.; Donnenberg, M.S. An Escherichia coli effector protein promotes host mutation via depletion of DNA mismatch repair proteins. mBio 2013, 4, e00152-13. [Google Scholar] [CrossRef] [PubMed]
  220. Kim, D.H.; Jin, Y.H. Intestinal bacterial beta-glucuronidase activity of patients with colon cancer. Arch. Pharm. Res. 2001, 24, 564–567. [Google Scholar] [CrossRef] [PubMed]
  221. Humblot, C.; Murkovic, M.; Rigottier-Gois, L.; Bensaada, M.; Bouclet, A.; Andrieux, C.; Anba, J.; Rabot, S. β-Glucuronidase in human intestinal microbiota is necessary for the colonic genotoxicity of the food-borne carcinogen 2-amino-3-methylimidazo [4, 5-f] quinoline in rats. Carcinogenesis 2007, 28, 2419–2425. [Google Scholar] [CrossRef]
  222. Mizumoto, A.; Ohashi, S.; Hirohashi, K.; Amanuma, Y.; Matsuda, T.; Muto, M. Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium. Int. J. Mol. Sci. 2017, 18, 1943. [Google Scholar] [CrossRef] [PubMed]
  223. Olsen, I.; Yilmaz, Ö. Possible role of Porphyromonas gingivalis in orodigestive cancers. J. Oral Microbiol. 2019, 11, 1563410. [Google Scholar] [CrossRef]
  224. Tan, X.; Banerjee, P.; Guo, H.F.; Ireland, S.; Pankova, D.; Ahn, Y.H.; Nikolaidis, I.M.; Liu, X.; Zhao, Y.; Xue, Y.; et al. Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11. J. Clin. Investig. 2017, 127, 117–131. [Google Scholar] [CrossRef]
  225. Vivant, A.L.; Garmyn, D.; Piveteau, P. Listeria monocytogenes, a down-to-earth pathogen. Front. Cell Infect. Microbiol. 2013, 3, 87. [Google Scholar] [CrossRef]
  226. Lauvau, G.; Vijh, S.; Kong, P.; Horng, T.; Kerksiek, K.; Serbina, N.; Tuma, R.A.; Pamer, E.G. Priming of memory but not effector CD8 T cells by a killed bacterial vaccine. Science 2001, 294, 1735–1739. [Google Scholar] [CrossRef]
  227. Huang, B.; Zhao, J.; Shen, S.; Li, H.; He, K.L.; Shen, G.X.; Mayer, L.; Unkeless, J.; Li, D.; Yuan, Y.; et al. Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res. 2007, 67, 4346–4352. [Google Scholar] [CrossRef] [PubMed]
  228. Duan, Y.; Ma, F.; Guo, B.; Chen, Z.; Liu, Y.; Jiang, X.; Rong, Z.; Zou, Y.; Zhang, H.; Wang, T.; et al. Listeria monocytogenes Promotes Breast Cancer Proliferation and Enhances the Survival Rate of Circulating Breast Cancer Cells. 2023. Available online: https://www.researchsquare.com/article/rs-2783293/v1 (accessed on 1 August 2024).
  229. Chua, M.D.; Mineva, G.M.; Guttman, J.A. Ube2N is present and functions within listeria Actin-rich structures and lamellipodia: A localization and pharmacological inhibition study. Anat. Rec. 2023, 306, 1140–1148. [Google Scholar] [CrossRef] [PubMed]
  230. Wu, X.; Zhang, W.; Font-Burgada, J.; Palmer, T.; Hamil, A.S.; Biswas, S.K.; Poidinger, M.; Borcherding, N.; Xie, Q.; Ellies, L.G.; et al. Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc. Natl. Acad. Sci. USA 2014, 111, 13870–13875. [Google Scholar] [CrossRef]
  231. Chen, Y.; Huang, Z.; Tang, Z.; Huang, Y.; Huang, M.; Liu, H.; Ziebolz, D.; Schmalz, G.; Jia, B.; Zhao, J. More Than Just a Periodontal Pathogen -the Research Progress on Fusobacterium nucleatum. Front. Cell Infect. Microbiol. 2022, 12, 815318. [Google Scholar] [CrossRef]
  232. Zhang, Y.; Zhang, L.; Zheng, S.; Li, M.; Xu, C.; Jia, D.; Qi, Y.; Hou, T.; Wang, L.; Wang, B. Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis. Gut Microbes 2022, 14, 2038852. [Google Scholar] [CrossRef]
  233. Li, G.; Sun, Y.; Huang, Y.; Lian, J.; Wu, S.; Luo, D.; Gong, H. Fusobacterium nucleatum-derived small extracellular vesicles facilitate tumor growth and metastasis via TLR4 in breast cancer. BMC Cancer 2023, 23, 473. [Google Scholar] [CrossRef] [PubMed]
  234. Franco, A.A.; Buckwold, S.L.; Shin, J.W.; Ascon, M.; Sears, C.L. Mutation of the zinc-binding metalloprotease motif affects Bacteroides fragilis toxin activity but does not affect propeptide processing. Infect. Immun. 2005, 73, 5273–5277. [Google Scholar] [CrossRef]
  235. Pradella, D.; Naro, C.; Sette, C.; Ghigna, C. EMT and stemness: Flexible processes tuned by alternative splicing in development and cancer progression. Mol. Cancer 2017, 16, 8. [Google Scholar] [CrossRef]
  236. Parida, S.; Wu, S.; Siddharth, S.; Wang, G.; Muniraj, N.; Nagalingam, A.; Hum, C.; Mistriotis, P.; Hao, H.; Talbot, C.C., Jr.; et al. A Procarcinogenic Colon Microbe Promotes Breast Tumorigenesis and Metastatic Progression and Concomitantly Activates Notch and β-Catenin Axes. Cancer Discov. 2021, 11, 1138–1157. [Google Scholar] [CrossRef]
  237. Fu, A.; Yao, B.; Dong, T.; Cai, S. Emerging roles of intratumor microbiota in cancer metastasis. Trends Cell Biol. 2023, 33, 583–593. [Google Scholar] [CrossRef] [PubMed]
  238. Rohrbeck, A.; Just, I. Cell Entry of C3 Exoenzyme from Clostridium botulinum. In Uptake and Trafficking of Protein Toxins; Barth, H., Ed.; Springer International Publishing: Cham, Switzerland, 2017; pp. 97–118. [Google Scholar]
  239. Gao, Y.; Shang, Q.; Li, W.; Guo, W.; Stojadinovic, A.; Mannion, C.; Man, Y.G.; Chen, T. Antibiotics for cancer treatment: A double-edged sword. J. Cancer 2020, 11, 5135–5149. [Google Scholar] [CrossRef]
  240. Wang, X.; Li, J.; Shi, W.; Huang, Z.; Xia, W.; Huang, J.; Su, Y.; Wang, S.; Shi, Y.; Bi, X.; et al. Efficacy of Moxifloxacin plus Treatment of Physician’s Choice in Patients with Metastatic Breast Cancer. Oncologist 2020, 25, e1439–e1445. [Google Scholar] [CrossRef] [PubMed]
  241. Ransohoff, J.D.; Ritter, V.; Purington, N.; Andrade, K.; Han, S.; Liu, M.; Liang, S.-Y.; John, E.M.; Gomez, S.L.; Telli, M.L.; et al. Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer. Nat. Commun. 2023, 14, 2053. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Potential origins of breast tissue/milk microbiota. (A) The structure of the human breast. Inset: the structure of the skin. (B) Three potential routes of microbial transfer to the breast milk/tissue. (1) Breast skin microbiota migration. Microbes of the adjacent skin could enter the mammary gland through the areola. (2) Infant mouth microbiota transfer. During suckling, the oral microbes of the infant could enter the mammary gland through retrograde transfer. (3) Gut–breast axis. Gut mucosal dendritic cells (DCs) occasionally sample commensal bacteria in the lumen and transfer them to lymphoid tissues and eventually reach the mammary gland.
Figure 1. Potential origins of breast tissue/milk microbiota. (A) The structure of the human breast. Inset: the structure of the skin. (B) Three potential routes of microbial transfer to the breast milk/tissue. (1) Breast skin microbiota migration. Microbes of the adjacent skin could enter the mammary gland through the areola. (2) Infant mouth microbiota transfer. During suckling, the oral microbes of the infant could enter the mammary gland through retrograde transfer. (3) Gut–breast axis. Gut mucosal dendritic cells (DCs) occasionally sample commensal bacteria in the lumen and transfer them to lymphoid tissues and eventually reach the mammary gland.
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Figure 2. Two major modes of bacterial translocation. (1) Luminal bacteria are internalized by specialized microfold (M) cells present in the gut epithelial layer. These bacteria are transcytosed and made available to mucosal immune cells. (2) Luminal bacteria are directly taken up by CD18+ phagocytic cells in the mucosal layer that penetrate the gut epithelial layer. These immune cells which have taken up bacteria migrate to gut-associated lymphoid tissues (GALTs) and then mesenteric lymph nodes, where they stay until they are disseminated to thymus, spleen, and other distant tissues.
Figure 2. Two major modes of bacterial translocation. (1) Luminal bacteria are internalized by specialized microfold (M) cells present in the gut epithelial layer. These bacteria are transcytosed and made available to mucosal immune cells. (2) Luminal bacteria are directly taken up by CD18+ phagocytic cells in the mucosal layer that penetrate the gut epithelial layer. These immune cells which have taken up bacteria migrate to gut-associated lymphoid tissues (GALTs) and then mesenteric lymph nodes, where they stay until they are disseminated to thymus, spleen, and other distant tissues.
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Figure 3. Roles of intratumoral bacteria in tumor metastasis. Bacteria inside the primary tumor could be transported to the metastasized tumor along with tumor cells. During metastasis, intratumoral bacteria assist the process in several different aspects. These include promotion of EMT, production of MMP, resistance to fluid sheer stress (FSS), and immune suppression. Arrows in different colors (yellow, red, and pink) indicate FSS at different locations.
Figure 3. Roles of intratumoral bacteria in tumor metastasis. Bacteria inside the primary tumor could be transported to the metastasized tumor along with tumor cells. During metastasis, intratumoral bacteria assist the process in several different aspects. These include promotion of EMT, production of MMP, resistance to fluid sheer stress (FSS), and immune suppression. Arrows in different colors (yellow, red, and pink) indicate FSS at different locations.
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Table 1. Bacteria differentially represented in normal vs. tumorous breast tissues.
Table 1. Bacteria differentially represented in normal vs. tumorous breast tissues.
Normal BreastBreast Cancer
MicrobesLevelsFunctionsRef.MicrobesLevelsFunctionsRef.
SphingomonasHigherDegrades environmental carcinogens, aromatic hydrocarbons, and polycyclic aromatic hydrocarbons; protective against ER+ breast cancer[24,28]Fusobacterium nucleatumHigherPromotes breast cancer cell attachment, invasion, and colonization during metastasis; impairs immunity and therapy response; activates β-catenin-mediated oncogene transcription and cell proliferation; produces β-lactamase for resistance to β-lactam antibiotics (e.g., penicillin)[24,29,30,31]
Firmicutes,
Actinobacteria
HigherNegatively correlate with stromal fibrosis and breast cancer risk; enriched in breast milk[32,33,34]
Lactobacillaceae, Acetobacterraceae,
Leuconostocaceae Xanthomonadaceae
HigherInduce fructose and mannose metabolism and immune-related genes; enriched in breast milk of healthy women[35,36,37]Enterobacteriaceae, StaphylococcusHigherInduce DNA double-strand breaks in host cells[38,39]
RalstoniaHigherDysregulates genes involved in carbohydrate metabolism[35]
CyanobacteriaHigherProduce anti-cancer molecules (e.g., Cryptophycin F)[40]Atopobium, GluconacetobacterHigherModulate immunological responses[24,41,42]
Proteobacteria, Synergistetes, TenericutesHigherRegulate milk composition and production[43,44]Porphyromonadaceae, RuminococcaceaeHigherParticipate in aberrant host metabolism[40,45,46]
Prevotellaceae,
Butyricimonas
HigherProduce short-chain fatty acids (SCFAs) (propionate and butyrate) that exert anti-tumor activities[40,47,48,49]Sutterella,
Verrucomicrobiaceae
HigherAlso found in cecal microbiota[40,50,51]
AcinetobacterHigherAbundant in HR+ and HER2+ breast cancer[40,52]
Flavobacterium,
Hydrogenophaga
HigherAbundant in metastatic breast cancer[40,53,54]
Alcaligenaceae, Moraxellaceae,
Parabacteroides
HigherEnriched in breast milk[40,55]Akkermansia (phylum Verrucomicrobia),
Thermia
HigherAbundant in TNBC[40,56]
Table 2. Representative bacteria in different types of tumors.
Table 2. Representative bacteria in different types of tumors.
Cancer TypesMicrobesLevelsPro-Tumor MechanismsRef.
Breast Fusobacterium nucleatumIncreasedSuppresses T cell infiltration into tumors; promotes tumor growth and metastatic progression[29]
Anaerococcus, Caulobacter Propionibacterium, Streptococcus, StaphylococcusDecreasedPositively correlated with oncogenic immune features and T-cell activation-related genes[9]
Bile ductBifidobacteriaceae, Enterobacteriaceae,
Enterococcaceae
IncreasedIncreased production of bile acids and ammonia, leading to DNA damage in host cells and carcinogenesis [88]
CervicalFusobacterium spp.IncreasedAssociated with increased IL-4 and TGF-β1 mRNA in cervical cells[89]
Anaerotruncus, Anaerostipes,
Atopobium, Arthrospira, Bacteroides, Dialister, Peptoniphilus, Porphyromonas, Ruminococcus,
Treponema
IncreasedElevates vaginal pH to weaken host defense against infection and promotes tumor formation[90]
ColorectalBacteroides fragilisIncreasedIncreased interleukin-17 in the colon and DNA damage in the colonic epithelium, accelerating tumor onset and elevating host mortality[91]
FusobacteriumIncreasedCancer cell proliferation and distant metastasis [80]
Esophageal Lactobacillus fermentumIncreasedEstablishes acidic environment for growth advantage[92]
Helicobacter pyloriIncreasedSpread from gastric colonization[92]
Campylobacter spp.IncreasedCauses inflammation that could contribute to carcinogenesis[93]
Porphyromonas gingivalisIncreasedAccelerates cell cycle and promotes cellular migration and metabolism of potentially carcinogenic substances such as ethanol to the carcinogenic derivative acetaldehyde [94]
Extrahepatic
Bile duct
Helicobacter pyloriIncreasedIncreases abundance of the virulence genes cagA and vacA and promotes tumor formation[89]
Helicobacter bilisIncreasedInduces inflammation to contribute to tumor formation[95]
Gallbladder Fusobacterium nucleatum, Escherichia coli, Enterobacter spp.IncreasedPromotes gallstone development and chronic cholecystitis to contribute to tumor formation[96]
GastricHelicobacter pyloriIncreasedCagA protein suppresses p53-mediated apoptosis of host cells while increasing cell motility and metastatic phenotypes[97]
Fusobacterium nucleatumIncreasedInduces epithelial-to-mesenchymal transition[98]
Liver cancerHelicobacter bifidusIncreasedContributes to formation of chronic hepatitis that promotes tumor progression[99]
LungAcidovorax spp.IncreasedAssociated with carcinomas with p53 mutations[100]
Thermus, LegionellaIncreasedAssociated with advanced-stage and metastatic cancer[101]
Oral cancerFusobacterium nucleatumIncreasedInduces epithelial-to-mesenchymal transition[98]
Firmicutes (esp. Streptococcus), Actinobacteria (esp. Rothia)IncreasedElevated in normal oral tissues[102]
Ovarian MycoplasmaIncreasedPrevalent in 60% of tumors[103]
PancreaticEnterobacteriaceae, Pseudomonas spp., Mycobacterium avium, Pseudoxanthomonas, Streptomyces, Bacillus cereusIncreasedContributes to chemotherapy resistance and immune suppression[104,105]
Malassezia globosaIncreasedInduces the complement cascade through the activation of mannose-binding lectin C3 to promote tumorigenesis [106]
Prostate Pseudomonas, Escherichia, Immunobacterium, Propionibacterium spp.IncreasedInduces prostatitis and differentiation of prostate basal cells into ductal cells to promote tumor formation[107]
Propionibacterium acnes spp.IncreasedInduces prostatitis and promotes tumor formation[108]
StaphylococcusIncreasedInduces inflammation of the prostate tissue and promotes tumor formation[107]
Fusobacterium nucleatum, Streptococcus oligosporusIncreasedInduces chemoresistance by regulating autophagy[109]
Table 3. Representative bacteria in different breast tumor subtypes.
Table 3. Representative bacteria in different breast tumor subtypes.
Breast Cancer
Subtypes
MicrobesLevelsRef.
Luminal AProteobacteria (Xanthomonadale)Increased[83]
Tenericutes, Proteobacteria, PlanctomycetesIncreased[110]
Luminal BFirmicutes (Clostridium)Increased[83]
Tenericutes, Proteobacteria, PlanctomycetesIncreased[110]
HER2+Thermi, Verrucomicrobia (Akkermasia)Increased[83]
Firmicutes (Granulicatella:US31), Bacteroidetes (Dyadobacter)Increased[26]
Firmicutes (Filibacter, Anaerostipes), Bacteroides (Cloacibacterium, Alloprevotella), Proteobacteria (PRD01a011B, Stakelama Blastomonas)Increased[9]
Proteobacteria (Burkholderiales, Helicobacter pylori)Increased[85]
TNBCStreptococcaceae, RuminococcusIncreased[83]
Actinomycetaceae, Caulobacteriaceae, Sphingobacteriaceae, Enterobacteriaceae, Prevotellaceae, Brucellaceae, Bacillaceae, Peptostreptococcaceae, FlavobacteriaceaeIncreased[86]
Prevotella, Brevundimonas, Actinomyces, Aerococcus, Arcobacter, Geobacillus, Orientia, Rothia, Streptococcaceae, Ruminococcus, EuryarchaeotaIncreased[83,86]
Bartonella, Coxiella, Mobiluncus, Mycobacterium, Rickettsia, Sphingomonas, Azomonas, Alkanindiges, Proteus, Brevibacillus, Kocuria, ParasediminibacteriumIncreased[68]
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Furuta, S. Microbiome—Stealth Regulator of Breast Homeostasis and Cancer Metastasis. Cancers 2024, 16, 3040. https://doi.org/10.3390/cancers16173040

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Furuta S. Microbiome—Stealth Regulator of Breast Homeostasis and Cancer Metastasis. Cancers. 2024; 16(17):3040. https://doi.org/10.3390/cancers16173040

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Furuta, S. (2024). Microbiome—Stealth Regulator of Breast Homeostasis and Cancer Metastasis. Cancers, 16(17), 3040. https://doi.org/10.3390/cancers16173040

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