Implications of the microbiome and metabolic intermediaries produced by bacteria in breast cancer

Abstract

The breast microbiome presents a diverse microbial community that could affects health and disease states, in the context of breast cancer. Sequencing technologies have allowed describing the diversity and abundance of microbial communities among individuals. The complex tumoral microenvironment that includes the microbial composition could influence tumor growth. The imbalance of diversity and abundance inside the microbial community, known as dysbiosis plays a crucial role in this context. One the most prevalent bacterial genera described in breast invasive carcinoma are Bacillus, Pseudomonas, Brevibacillus, Mycobacterium, Thermoviga, Acinetobacter, Corynebacterium, Paenibacillus, Ensifer, and Bacteroides. Paenibacills genus shows a relation with patient survival. When the Paenibacills genus increases its abundance in patients with breast cancer, the survival probability decreases. Within this dysbiotic environment, various bacterial metabolites could play a pivotal role in the progression and modulation of breast cancer. Key bacterial metabolites, such as cadaverine, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO), have been found to exhibit potential interactions within breast tissue microenvironments. Understanding the intricate relationships between dysbiosis and these metabolites in breast cancer may open new avenues for diagnostic biomarkers and therapeutic targets. Further research is essential to unravel the specific roles and mechanisms of these microbial metabolites in breast cancer progression.

Keywords:
Microbiome; cancer; breast cancer; dysbiosis; bacterial metabolites

Breast cancer

According to the World Health Organization (WHO), breast cancer is considered one of the most prevalent tumors worldwide, with over 2.2 million new cases reported and more than 685,000 women deaths in 2020 (WHO, 2023). Breast cancer is a non-communicable chronic ailment that originates when cells within breast tissue lose their ability to regulate their normal growth and division, resulting in uncontrolled proliferation. This unregulated cell multiplication leads to aberrant proliferation, marking the initiation of a carcinogenesis process. Breast cancer is an intricately heterogeneous disease, comprising established subtypes with significant variability in the progression of the disease within each subtype. Presently, breast carcinoma is categorized into four molecular classes: luminal A, luminal B, HER2 (Human epidermal growth factor receptor 2), and triple-negative (TN) with basal and non-basal phenotypes (Calderón Del Valle and Gallón Villega, 2012; Fernández and Reigosa, 2016).

The majority of breast cancer cases are sporadic, meaning they lack a specific hereditary pattern, with genetic, epigenetic, and genomic changes predominantly occurring in somatic cells. It is estimated that only 5 to 10% of breast carcinomas are considered hereditary syndromes, with these alterations potentially being passed between generations as an autosomal dominant disease (Calderón Del Valle and Gallón Villega, 2012). Syndromes associated with this type of tumor are characterized by early onset, vertical transmission of genetic risk factors, bilateral tumor presentation in both breasts and instances of other cancers within the same family (Calderón Del Valle and Gallón Villega, 2012; Fernández and Reigosa, 2016). The hereditary pattern of breast carcinoma is linked to various high-penetrance genes, such as BRCA1 and BRCA2.

However, the genesis of many cancerous processes cannot be solely attributed to genetic changes, as environmental factors play a substantial role in these mechanisms. The microbiome is one such factor (Álvarez-Mercado et al., 2023). The relationship of the microbiome with the development of specific cancers such as colorectal and gastric cancer has been broadly evidenced, however, there has been a growing focus on the proposed link between the microbiome and breast cancer. This review explores the recent association between the microbiome and breast cancer, acknowledging the emerging dimensions of cancer hallmarks, particularly in the context of polymorphic microbiomes (Hanahan, 2023).

Microbiome

The human microbiome comprises a complex assembly of microorganisms - bacteria, viruses, fungi, protozoa, and archaea - that coexist in various regions of the human body, including the skin, oral mucosa, vagina, lungs, and predominantly the gastrointestinal system (Karen, 2008). These microorganisms exhibit a spectrum of effects, ranging from beneficial to harmful or neutral (Cheng et al., 2020), collectively contributing to the body’s overall equilibrium, including reinforcing the body’s defenses and facilitating nutrient metabolism. The gastrointestinal tract hosts the most expansive and diverse human-associated microbiome, housing trillions of microorganism cells and an extensive array of species (Sender et al., 2018). Alterations in the diverse landscape of the gut microbiome, known as “dysbiosis”, are recognized as pivotal factors in the development of both metabolic diseases and cancer. Recent studies have highlighted a connection between the intestinal microbiome and various intestinal diseases, notably colorectal cancer (CRC). While these changes in the gut microbiome, observed in individuals with CRC, are not definitively causal in carcinogenesis, they are substantive enough to serve as diagnostic indicators and, in certain cases, prognostic markers for this cancer (Saus et al., 2019).

For instance, specific bacterial species, such as Fusobacterium nucleatum, Bacteroides fragilis, and Enterococcus faecalis, have been associated with consequential changes in the intestinal epithelium, instigating an inflammatory response that can incite DNA damage and local cell proliferation (Saus et al., 2019). Moreover, CRC patients exhibit a heightened presence of proinflammatory opportunistic bacteria and microbes associated with metabolic disorders. Species like F. nucleatum, Streptococcus gallolyticus, Escherichia coli, B. fragilis, and E. faecalis are predominant in collected fecal samples from CRC patients. At the same time, genera like Roseburia, Clostridium, Faecalibacterium, and Bifidobacterium are comparatively scarce in individuals with CRC (Saus et al., 2019). These microbial shifts are observed as significant contributors to the pathogenesis of CRC.

Dysbiosis in the context of cancer development

Dysbiosis is a state characterized by persistent imbalance in the microbiome, primarily in the gut, which typically plays a beneficial role in maintaining the body’s health (DeGruttola et al., 2016). This imbalance can give rise to various health conditions including obesity, inflammatory bowel disease (IBD), and even cancer (DeGruttola et al., 2016). Dysbiosis involves a notable alteration in the composition of the microbiome, surpassing what is considered normal for a specific group of subjects under study and it is typically characterized by three key elements. First, an increase in harmful bacteria (Zhang et al., 2022). Second, a decrease in beneficial bacteria (Korem et al., 2015), and third a reduction in microbiome diversity (Kostic et al., 2015). Additionally, it can be triggered by a myriad of factors (Levy et al., 2017), including infections and inflammations (Zhang et al., 2022), dietary choices, and exposure to foreign chemicals (Norman et al., 2015; Sonnenburg et al., 2016), genetic influences (Levy et al., 2015), and hereditary predispositions (Stappenbeck and Virgin, 2016).

The complex interplay of the microbiome significantly affects host cell growth, programmed cell death, immune response modulation, and the metabolism of indigestible dietary components, xenobiotics, and pharmaceuticals (Parida and Sharma, 2019). Several studies have attempted to define the composition of a core healthy microbiome to understand the pathological mechanisms underlying diseases such as cancer and inflammatory disorders within dysbiotic scenarios. While only a few specific microbes are established as direct causative agents of cancer (e.g., Helicobacter pylori), numerous microbes appear to contribute to cancer progression through modulation of the host’s immune system. Certain microbes possess immunostimulatory properties that hold significant implications for cancer development and the immune surveillance of tumors (Sepich-Poore et al., 2021). An exemplary case is a strong association between the Gram-negative bacteria F. nucleatum and colorectal cancer, evident in abundance within tumor tissues and pre-cancerous adenomas, particularly in high-grade dysplasia tumors (Sheflin et al., 2014). The role of the microbiome extends beyond solid tumors to encompass cancers such as leukemia. Preclinical investigations in mice have revealed a probable correlation between specific genetic predispositions leading to leukemia and consequential alterations in the intestinal microbiome in these animals (Dueñas et al., 2020). Nycz et al. (2018) scrutinized stool samples from 42 pediatric leukemia patients at various treatment stages unveiling microbial changes over time and under diverse treatment conditions (Nycz et al., 2018). Similar studies enabled the observation of gut bacterial composition alterations as treatment progressed in pediatric leukemia patients (Wang et al., 2014; Tidjani et al., 2016). For instance, bacterial groups like Clostridiaceae and Bacteroidaceae dominate in healthy children (Wang et al., 2014; Tidjani et al., 2016), but in cases of acute lymphoblastic leukemia, the Bacteroidaceae groups are more abundant at diagnosis while the Clostridiaceae and Lachnospiraceae groups decrease (Tidjani et al., 2016). While studies have not yet demonstrated that changes in individual’s microbiota composition leads to the development of leukemia, for example, it is already known that the microbiota could be altered with the progression of treatments as a side effect or rather could be affected by genetics predispositions.

These findings underscore the substantial influence of dysbiosis in shaping the microbiome’s association with cancer development, whether it involves solid tumors such as colorectal cancer or hematologic malignancies like leukemia. Understanding these dynamic interactions between the microbiome and cancer progression is vital for advancing potential therapeutic strategies and diagnostic approaches.

Breast microbiome and breast cancer

In the context of breast cancer, the diverse and distinctive bacterial community present in the female mammary gland stands out in comparison to other bodily sites. Notably, this community remains independent of age, pregnancy, or geographical origin (Urbaniak et al., 2014). Emerging evidence strongly suggests that part of the breast tissue microbiome originates from translocation either from the gastrointestinal tract or through the skin, primarily via the areola-nipple openings, oral-nipple contact during breastfeeding, or potentially even through sexual contact. It is theorized that this mammary microbiome contributes significantly to the preservation of healthy breast tissue by, for instance, activating resident immune cells. Additionally, the specific type of bacteria and their metabolic activity, particularly their ability to degrade potential carcinogens, might play a crucial role in this context (Urbaniak et al., 2014).

Advanced sequencing technologies and insights gained from the Human Microbiome Project have revealed that the diversity and abundance of microbial communities vary significantly among individuals (Human Microbiome Project Consortium, 2012). There is a prevailing hypothesis that the breast microbiome could directly influence the risk of developing breast cancer. While this hypothesis suggests various pathways for disease alterations and progression, it does not conclusively identify a specific microbial pattern responsible for breast carcinogenesis (Urbaniak et al., 2014; Urbaniak et al., 2016).

The breast shows a sophisticated microenvironment that comprises complex systems including epithelial, interstitial, and mucosal immune systems (Going and Moffat, 2004). Microbial exposure induces the modulation of the immune system and its mucosa, where inflammation processes could happen facing changes in the microenvironment present in those tissues induced by bacterial infections (Schwabe and Jobin, 2013). Thus, the presence of altered immune responses in the breast microenvironment could be through the influence of the mammary microbial community and its deviations.

Currently, normal breast tissue hosts a dominant microbial community inclusive of Proteobacteria, Firmicutes (Urbaniak et al., 2014), Sphingomonas yanoikuyae (Xuan et al., 2014), Actinobacteria (Thompson et al., 2017), Methylobacterium (Wang et al., 2017), Ralstonia (Constantini et al., 2018), Bacteroidaceae (Meng et al., 2018), Prevotella, Lactococcus, Streptococcus, Corynebacterium, Staphylococcus (Urbaniak et al., 2016), and an unclassified genus of the family Sphingomonadaceae (Chan et al., 2016). The higher prevalence of Proteobacteria and Firmicutes in comparison to other taxonomic groups could stem from microbial adaptation to the fatty acid-rich tissue environment (Figure 1).

Figure 1 -
Bacterial composition commonly found in breast cancer tissue and bacterial metabolites produced in breast dysbiosis conditions.

Dysbiosis of the microbiome in breast cancer

The microenvironment in and around tumors encompasses a diverse array of cell types, including the microbiome. The physiological and pathological changes occurring in these cells, as well as the microbial composition, significantly influence tumor growth. Dysbiosis, characterized by the disruption of normal microbial community function and the breakdown of symbiotic relationships within this community, plays a pivotal role in this context.

An analysis conducted by Xuan et al. (2014) highlighted important findings regarding bacterial quantity between normal tissue and breast cancer patients. Interestingly, they determined that the number of Operational Taxonomic Units (OTUs) remained consistent between normal tissue and tumor, indicating no significant variations. However, it is notable that breast tumor tissue exhibited significantly reduced quantities of bacteria, and the community uniformity differed significantly (p = 0.01). From the 1614 OTUs detected, 11 were differentially abundant (p < 0.05), with eight more prevalent in paired normal tissue and three more abundant in tumor tissue (Xuan et al., 2014). The study observed notable differences in the genera Methylbacterium and Sphingomonas between adjacent tissue and tumor tissue, indicating a potential role for these bacteria in cancer development. Methylobacterium radiotolerans was found to be the most prevalent bacteria in tumor tissue, present in 100% of the samples. Conversely, Sphingomonas yanoikuyae was found in 95% of the samples and exhibited significantly higher absolute levels in normal tissue. Intriguingly, Sphingomonas yanoikuyae was absent in the corresponding tumor tissue. The relative abundances of these two bacterial species inversely correlated in normal breast tissue but not in tumor tissue, suggesting a link between dysbiosis and breast cancer. Notably, M. radiotolerans was present in all samples, with its absolute levels showing no significant variance between normal tissue and tumor tissue. This suggests that the higher relative abundance of M. radiotolerans in the tumor reflects a decrease in other co-existing bacteria rather than an increase in the organism’s absolute levels (Xuan et al., 2014).

Understanding the breast microbiome in breast cancer studies

Numerous studies have analyzed the breast microbiome highlighting the predominance of the Proteobacteria and Firmicutes phyla, underscoring their substantial presence, although with some variations. Urbaniak et al. (2014) conducted an extensive investigation to discern the specific microbiome within breast tissue. Examining a sizeable cohort of women of Irish and Canadian descent with and without breast cancer, they uncovered a diverse bacterial population across all tissues studied. Among the most abundant phyla observed in breast tissue were Proteobacteria and Firmicutes, which these two groups of bacteria were more representative than other taxonomic groups. The authors postulated that these findings could be attributed to a probable microbial adaptation to the fatty acid-rich environment of breast tissue. Notably, the principal OTUs were associated with seven distinct phyla: Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, Deinococcus thermus, Verrucomicrobia, and Fusobacteria, with Proteobacteria being the most prevalent, followed by Firmicutes.

In a subsequent study by Urbaniak et al. (2016), they found differing bacterial profiles in breast tissue among healthy women and those diagnosed with breast cancer. Similarly, Hieken et al. (2016) noted significant distinctions in the breast microbiome of women with benign conditions compared to those with malignant tumors. Comparing adjacent tissue from women with breast cancer to that of healthy counterparts, they identified significantly higher relative abundances of specific bacterial genera in each group. Healthy patients exhibited a prevalence of Prevotella, Lactococcus, Streptococcus, Corynebacterium, and Micrococcus, while breast cancer patients have showcased higher levels of Bacillus, Staphylococcus, Enterobacteriaceae, Comamondaceae, and Bacteroidetes. Notably, the latter group’s bacteria demonstrated the ability to induce DNA damage in vitro (Hieken et al., 2016).

Thompson et al. (2017) characterized the breast microbiome in 668 breast tumor tissues and 72 adjacent non-cancerous tissues, unveiling potential alterations in the microbial composition among different disease subtypes. Predominant phyla in tumor sites included Proteobacteria (48.0%), Actinobacteria (26.3%), and Firmicutes (16.2%), aligning with prior findings. Differentially abundant species observed in tumor samples were Mycobacterium fortuitum and Mycobacterium phlei. Moreover, Proteobacteria exhibited a higher prevalence in tumor tissues, whereas Actinobacteria were more prevalent in non-cancerous adjacent tissue samples (Thompson et al., 2017).

Another study conducted by Kim et al. (2021) showed the potential involvement of the microbiome in breast tumor progression. Analyzing 114 samples from Korean breast cancer patients - comprising tumor, adjacent normal, and lymph node tissues - they noted microbial divisions into two clusters without discernible differences among the tissues studied. Notably, the microbiome’s categorization into these clusters was correlated with clinicopathologic factors like the risk of regional recurrence, showing the potential impact of Enterococcus spp. in shaping these differences (Kim et al., 2021).

Tzeng et al. (2021) employed 16S rRNA gene sequencing to analyze the human breast tissue microbiome across 221 breast cancer patients, 18 individuals prone to breast cancer, and 69 control subjects, revealing substantial insights. Their findings highlighted noteworthy differences in the relative abundance of multiple bacterial genera when stratified across distinct breast tissue types, cancer stages, grades, histological subtypes, and other clinical factors. Of particular significance was the absence of Anaerococcus, Caulobacter, and Streptococcus - found prevalent in benign tissue - in the cancer-associated tissue. Furthermore, the investigation identified Proteobacteria as the dominant bacterial phylum in breast tissues, followed by Firmicutes and Actinobacteria. Their analysis unveiled a lower abundance of Enterobacteriaceae alongside a higher prevalence of Corynebacterium, Lactococcus, and Streptococcus in breast tissue obtained from healthy individuals instead of those afflicted by cancer. These findings contribute significantly to our understanding of the distinct microbial compositions associated with breast cancer, offering potential avenues for further research and clinical implications.

The Bacteria in Cancer (BIC) Database harbors data from The Cancer Genome Atlas (TCGA), which includes bacteria expression profiles from whole genome sequencing (WGS), and whole exon sequencing (WXS) (Kai-Pu et al., 2023). This database shows the ten most prevalent bacterial genera in breast invasive carcinoma (BRCA) such as Bacillus, Pseudomonas, Brevibacillus, Mycobacterium, Thermoviga, Acinetobacter, Corynebacterium, Paenibacillus, Ensifer and Bacteroides. Regarding clinical importance, two genera stand out from those mentioned above Corynebacterium and Paenibacillus. Corynebacterium genus shows that relative abundance is very expressive in normal tissue in comparison to the tumor tissue (p = 7.105e-18). Paenibacills genus shows a relation with patient survival. When the Paenibacills genus increases its abundance in patients with breast cancer, the survival probability survival decreases to around 30% (p = 1.545e-02).

Bacterial metabolites and their potential role in cancer

The evolution of scientific inquiry has tirelessly sought to discover, quantify, and define analytes - commonly recognized as cancer biomarkers - pivotal in the clinical landscape. Notably, these biomarkers, like CA15-3/CA27.29, CA27.29, BRCA1, and BRCA2, are detectable in various bodily fluids and hold substantial clinical utility, particularly in the context of breast cancer diagnosis and prognosis (National Cancer Institute, 2023).

Breast cancer development is a multistep process that includes multiple oncopathological and inflammatory processes. These intricate mechanisms, when disrupted by dysbiosis, could induce fluctuations in the production of certain metabolites. These metabolites might crucially affect the modulation of breast cancer. Conversely, maintaining a state of intestinal microbiome homeostasis appears to trigger the release of metabolites exhibiting anti-metastatic potential - a promising pathway for potential therapeutic ways (Figure 2). Consequently, the exploration of microbiome-generated metabolites has emerged as an area of scientific interest. Their potential interactions with transcriptional, epigenetic, and metabolic processes within oncology present a captivating frontier for further investigation (Luu and Visekruna, 2021).

Figure 2 -
Description of bacterial metabolites produced in breast microbiome dysbiosis.

A primary signaling conduit linking the microbiome and the host involves the secretion of microbial metabolites that traverse the circulatory system and are directed to specific target cells. (Burcelin et al., 2013). Functionally similar to human hormones, these microbial metabolites exhibit a capacity for biological transmission and action. Moreover, these compounds infiltrate the circulation, influencing and modulating the intestine and other local environments, thereby influencing their function and dynamics (Mikó et al., 2019). This perspective highlights the important role of microbial metabolites in cancer modulation. Its potential effects on diverse biological processes across oncological domains underscore the need for comprehensive exploration and understanding within this complex interplay.

Trimethylamine N-oxide (TMAO)

Various microbial species, particularly Desulfovibrio and Desulfovibrio desulfuricans, are known for their ability to convert dietary components like choline into Trimethylamine (TMA) through specific enzymatic pathways, ultimately leading to the production of Trimethylamine N-oxide (TMAO) (Zeisel and Warrier, 2017). This conversion typically occurs following the intake of foods rich in choline and L-carnitine, such as red meat or eggs, which serve as primary sources for these precursors (Demarquoy et al., 2004).

TMAO has been attributed with diverse biological functions, including countering the denaturing effects of pH, elevating osmotic pressure, and stabilizing proteins similar to a molecular chaperone. Additionally, it has implications for lipid metabolism, modulating oxidative stress (Zeisel and Warrier, 2017), and potentially affecting the anti-tumoral immune response mediated by CD8+ T cells (Wang et al., 2022). Specifically in breast cancer, TMAO’s influence on α-casein is recognized as a tumor-suppressing chaperone present in the milk of various mammals (Bhat et al., 2017). This interaction underscores the multifaceted impact of TMAO on cellular mechanisms relevant to breast cancer development and progression, suggesting a potential pathway for further exploration in understanding its specific role in oncological processes.

Cadaverine

Cadaverine, also recognized as 1,5-diaminopentane, is a natural polyamine generated by the decarboxylation of L-lysine facilitated by lysine decarboxylase, a specific enzyme. This molecule is naturally present in a wide spectrum of both prokaryotic and eukaryotic organisms. The compound exhibits diverse biological properties and holds significant importance in cell survival, particularly in acidic environments, offering protection to cells in anaerobic conditions lacking inorganic phosphate (Pi) (Moreau, 2007). While human cells can also produce cadaverine, bacterial synthesis predominantly contributes to its presence. Notably, various intestinal bacteria such as Shigella flexneri, Shigella sonnei, Escherichia coli, and the Streptococcus genus are known to express enzymes involved in its biosynthesis (de las Rivas et al., 2006).

Remarkably, studies by Kovács et al. (2019a) observed a reduction in cadaverine levels within the intestinal environment associated with breast cancer development. Intriguingly, in experimental models involving rats transplanted with 4T1 breast cancer cell lines, administration of cadaverine (at 500 nmol/kg) contributed to the reversal of endothelial to mesenchymal transition, thus reducing tumor aggressiveness (Kovács et al., 2019a). This insight implies that dysbiosis in the gut microbiome may potentially diminish agents such as cadaverine, which could otherwise play a protective role against processes associated with carcinogenesis. However, additional research in this area is necessary to uncover direct relationships between cadaverine and its impact on cancer pathways.

Lithocholic Acid (LCA)

Lithocholic acid (LCA) is a secondary bile acid produced through the enzymatic activity of 7α/β-hydroxysteroid dehydroxylase (baiH gene), playing a cytostatic role in breast cancer. Synthesized by the dehydroxylation of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) at position 7 (Long et al., 2017), LCA is primarily generated by anaerobic bacteria, particularly Clostridiales, which facilitate the transformation of bile acids. The genes responsible for the degradation of secondary bile acids are part of the bile acid-inducible (bai) operon (Ridlon et al., 2006).

LCA exerts anticancer effects through the Takeda G protein-coupled receptor 5 (TGR5). Research conducted by Mikó et al. (2018) revealed that patients diagnosed with early-stage breast cancer exhibited reduced serum levels of lithocholic acid compared to the control group. This reduction in LCA levels, along with variations in bile acid ratios and decreased expression of the baiH gene in fecal DNA, suggests the diminished generation of LCA by the intestinal microbiome in early-stage breast cancer (Mikó et al., 2018).

Furthermore, Kovács et al. (2019b) demonstrated that the application of LCA to breast cancer cells resulted in increased expression of Kelch-like ECH-associated protein 1 (KEAP1) and reduced expression of nuclear factor 2 (NRF2). This was achieved via the activation of TGR5 and constitutive androstane receptor (CAR), affecting antioxidant enzyme expression, such as glutathione peroxidase 3 (GPX3), and leading to increased oxidative stress. Pharmacological induction of NRF2 with antioxidants reversed these effects, suggesting the cytostatic impact of LCA due to the imbalance between pro- and antioxidants. As breast cancer progressed, components of the cytostatic pathway triggered by LCA displayed gradual reduction, and this loss was associated with a poor prognosis (Kovács et al., 2019b).

Lipopolysaccharides (LPS)

Studies that analyze the implications of intratumoral bacteria in tumorigenesis, particularly through DNA damage and tumor progression, have increased in the last decade. Specific bacteria, notably those in the Enterobacteriaceae family producing colibactin, have been associated with causing DNA damage and promoting tumorigenesis (Nougayrède et al., 2006; Pleguezuelos-Manzano et al., 2020). While mammary tissues host various commensal bacteria, the link between mammary tumor growth and differential bacterial distribution remains largely unexplored. In a metagenomic analysis conducted by Wilkie et al. (2022) employing a mouse model to assess the microbiome’s association with breast tumor growth, several key findings emerged (Wilkie et al., 2022). The study revealed a substantial increase in Gram-negative bacterial populations in late-stage tumors (LST) and late-stage tumors with dextran sodium sulfate (LSTDSS) compared to control skin samples or early-stage mammary tumors. Notably, higher LPS amounts were detected in the control samples. Furthermore, an increased abundance of Gram-negative bacterial populations was observed in LST and LSTDSS mammary tumors, with no significant difference in abundance between them. Importantly, the study showcased the influence of LPS on the expression of S100A7 (S100 calcium-binding protein A7 or psoriasin), a microbicide protein associated with breast cancer progression and metastasis. Overexpression of S100A7 induced mammary gland hyperplasia and recruited tumor-associated macrophages, and this study highlighted a novel role of LPS in driving S100A7 expression. The findings imply the modulation of the expression of TLR4 and RAGE in invasive breast cancers (Wilkie et al., 2022).

Risk of describing microbiome studies

It is important to emphasize the risks that may arise from trials using next-generation sequencing techniques in microbiome studies, which must be approached with the utmost caution, always aiming to use blank samples and minimize any contamination caused by sample manipulation that could affect the microbiome composition.

Conclusion

Understanding the intricate relationship between the microbiome, dysbiosis, and associated bacterial metabolites like LPS, cadaverine, and TMAO could be pivotal in comprehending breast cancer progression. The complex interaction between the microbiome and the host influences various physiological processes, immune responses and metabolic pathways, mainly when there is an imbalance in the microorganisms of this community that leads to dysbiosis. Furthermore, dysbiosis has been correlated with pathological processes, including breast cancer, underscoring the importance of investigating microbial alterations.

Additionally, metabolites produced by the microbiome, such as LPS, cadaverine, and TMAO, have shown the potential to influence molecular, metabolic, and immunological processes, thereby potentially impacting breast cancer pathogenesis. LPS has been associated with S100A7 expression and tumor progression, while metabolites like cadaverine and TMAO exhibit complex interactions with cancer cells and tumor microenvironments, influencing cellular behavior and tumor growth.

The study of these components provides valuable information on potential diagnostic biomarkers, therapeutic targets, and understanding of the intrinsic mechanisms of breast cancer. A deeper exploration of these microbiome-related factors and metabolites holds promise for unveiling novel pathways in breast cancer research, potentially leading to innovative diagnostic methods and therapeutic interventions.

Acknowledgements

The authors thank the Chilean Society of Genetics for their support in preparing this manuscript

References

• Álvarez-Mercado AI, Del Valle AC, Fernández MF and Fontana L (2023) Gut microbiota and breast cancer: The dual role of microbes. Cancers (Basel) 15:443.
• Bhat MY, Singh LR and Dar TA (2017) Trimethylamine N-oxide abolishes the chaperone activity of α-casein: An intrinsically disordered protein. Sci Rep 7:6572.
• Burcelin R, Serino M, Chabo C, Garidou L, Pomié C, Courtney M, Amar J and Bouloumié A (2013) Metagenome and metabolism: The tissue microbiota hypothesis. Diabetes Obes Metab Suppl 3:61-70.
• Calderón Del Valle AS and Gallón Villega LJ (2012) Cáncer de mama asociado a mutaciones genéticas de los BRCA 1 y 2. Res Ces Med 26:185-199.
• Chan AA, Bashir M, Rivas MN, Duball K, Sieling PA, Pieber TR, Vaishampaya PA, Love SM and Lee DJ (2016) Characterization of the microbiome of nipple aspirate fluid of breast cancer survivors. Sci Rep-UK 6:28061.
• Cheng H, Wang C, Cui L, Wen Y, Chen X, Gong F and Yi H (2020) Opportunities and challenges of the human microbiome in ovarian cancer. Front Oncol 10:163-173.
• Constantini L, Magno S, Albanese D, Donati C, Molinari R, Filippone A, Masetti R and Merendino N (2018) Characterization of human breast tissue microbial community from core needle biopsies through the analysis of multi hypervariable 16S-rRNA gene regions. Sci Rep 8:16893.
• DeGruttola AK, Low D, Mizoguchi A and Mizoguchi E (2016) Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis 22:1137-1150.
• de las Rivas B, Marcobal A, Carrascosa AV and Muñoz R (2006) PCR detection of foodborne bacteria producing the biogenic amines histamine, tyramine, putrescine, and cadaverine. J Food Prot 69:2509-2514.
• Demarquoy J, Georges B, Rigault C, Royer MC, Clairet A, Soty M, Lekounoungou S and Le Borgne F (2004) Radioisotopic determination of l-carnitine content in foods commonly eaten in Western countries. Food Chem 86:137-142.
• Dueñas VC, Janssen S, Oldenburg M, Auer F, González-Herrero I, Casado-García A, Isidro-Hernández M, Raboso-Gallego J, Westhoff P, Pandyra AA et al (2020) An intact gut microbiome protects genetically predisposed mice against leukemia. Blood 136:2003-2017.
• Fernández AT and Reigosa AY (2016) Cáncer de mama hereditario. Comunidad y Salud 14:52-60.
• Going JJ and Moffat DF (2004). Escaping from flatland: Clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol 203:538-544.
• Hanahan D (2023) Hallmarks of cancer: New dimensions. Cancer Discov 12:31-46.
• Human Microbiome Project Consortium(2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207-214.
• Hieken TJ, Chen J, Hoskin TL, Walther-Antonio M, Johnson S, Ramaker S, Xiao J, Radisky DC, Knutson KL, Kalari KR et al (2016) The microbiome of aseptically collected human breast tissue in benign and malignant disease. Sci Rep 6:30751.
• Kai-Pu C, Chia-Lang H, Yen-Jen O, Hsuan-Cheng H and Hsueh-Fen J (2023) BIC: A database for the transcriptional landscape of bacteria in cancer. Nucleic Acids Res 61:D1205-D1211.
• Karen H(2008) Good bugs, bad bugs: Learning what we can from the microorganisms that colonize our bodies. J Clin Invest 118:3817.
• Kim HE, Kim J, Maeng S, Oh B, Hwang KT and Kim BS (2021) Microbiota of breast tissue and its potential association with regional recurrence of breast cancer in korean women. J Microbiol Biotechnol 31:1643-1655.
• Korem T, Zeevi D, Suez J, Weinberger A, Avnit-Sagi T, Pompan-Lotan M, Matot E, Jona G, Harmelin A, Cohen N et al (2015) Growth dynamics of gut microbiota in health and disease inferred from single metagenomic samples. Science 349:1101-1106.
• Kostic AD, Gevers D, Siljander H, Vatanen T, Hyötyläinen T, Hämäläinen AM, Peet A, Tillmann V, Pöhö P, Mattila I et al (2015) The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17:260-273.
• Kovács T, Mikó E, Vida A, Sebő É, Toth J, Csonka T, Boratkó A, Ujlaki G, Lente G, Kovács P et al (2019a) Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors. Sci Rep 9:1300.
• Kovács P, Csonka T, Kovács T, Sári Z, Ujlaki G, Sipos A, Karányi Z, Szeőcs D, Hegedűs C, Uray K et al (2019b) Lithocholic acid, a metabolite of the microbiome, increases oxidative stress in breast cancer. Cancers (Basel) 11:1255.
• Levy M, Kolodziejczyk AA, Thaiss CA and Elinav E (2017) Dysbiosis and the immune system. Nat Rev Immunol 17:219-232.
• Levy M, Thaiss CA, Zeevi D, Dohnalová L, Zilberman-Schapira G, Mahdi JA, David E, Savidor A, Korem T, Herzig Y et al (2015) Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163:1428-1443.
• Long SL, Gahan CGM and Joyce SA (2017) Interactions between gut bacteria and bile in health and disease. Mol Aspects Med 56:54-65.
• Luu M and Visekruna A (2021) Microbial metabolites: Novel therapeutic tools for boosting cancer therapies. Trends Cell Biol 31:873-875.
• Meng S, Chen B, Yang J, Wang J, Zhu D, Meng Q and Zhang L (2018) Study of microbiomes in aseptically collected samples of human breast tissue using needle biopsy and the potential role of in situ tissue microbiomes for promoting malignancy. Front Oncol 8:318.
• Mikó E, Kovács T, Sebő É, Tóth J, Csonka T, Ujlaki G, Sipos A, Szabó J, Méhes G and Bai P (2019) Microbiome-microbial metabolome-cancer cell interactions in breast cancer-familiar, but unexplored. Cells 8:293.
• Mikó E, Vida A, Kovács T, Ujlaki G, Trencsényi G, Márton J, Sári Z, Kovács P, Boratkó A, Hujber Z et al (2018) Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg 1859:958-974.
• Moreau PL (2007) The lysine decarboxylase CadA protects Escherichia coli starved of phosphate against fermentation acids J Bacteriol 189:2249-2261.
• Norman JM, Handley SA, Baldridge MT, Droit L, Liu CY, Keller BC, Kambal A, Monaco CL, Zhao G, Fleshner P et al (2015) Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160:447-460.
• Nougayrède JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, Buchrieser C, Hacker J, Dobrindt U and Oswald E (2006) Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313:848-851.
• Nycz BT, Dominguez SR, Friedman D, Hilden JM, Ir D, Robertson CE and Frank DN (2018) Evaluation of bloodstream infections, Clostridium difficile infections, and gut microbiota in pediatric oncology patients. PLoS One 13:e0191232.
• Parida S and Sharma D (2019) The power of small changes: Comprehensive analyses of microbial dysbiosis in breast cancer. Biochim Biophys Acta Rev Cancer 1871:392-405.
• Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, Gurjao C, Manders F, Dalmasso G, Stege PB et al (2020) Mutational signature in colorectal cancer caused by genotoxic pks⁺ E. coli Nature 580:269-273.
• Ridlon JM, Kang DJ and Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47:241-259.
• Saus E, Iraola-Guzmán S, Willis JR, Brunet-Vega A and Gabaldón T (2019) Microbiome and colorectal cancer: Roles in carcinogenesis and clinical potential. Mol Asp Med 69:93-106.
• Schwabe RF and Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13:800-812.
• Sender R, Fuchs S and Milo R (2018) Revised estimates for the number of human and bacteria cells in the body. PLoS Biol 14:e1002533
• Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA and Knight R (2021) The microbiome and human cancer. Science 371:eabc4552.
• Sheflin AM, Whitney AK and Weir TL (2014) Cancer-promoting effects of microbial dysbiosis. Curr Oncol Rep 16:406.
• Sonnenburg ED, Smits SA, Tikhonov M, Higginbottom SK, Wingreen NS and Sonnenburg JL (2016) Diet-induced extinctions in the gut microbiota compound over generations. Nature 529:212-215.
• Stappenbeck TS and Virgin HW (2016) Accounting for reciprocal host-microbiome interactions in experimental science. Nature 534:191-199.
• Thompson KJ, Ingle JN, Tang X, Chia N, Jeraldo PR, Walther-Antonio MR, Kandimalla KK, Johnson S, Yao JZ, Harrington SC et al (2017) A comprehensive analysis of breast cancer microbial community and host gene expression. PLoS One 12:e0188873.
• Tidjani Alou M, Lagier JC and Raoult D (2016) Diet influence on the gut microbiota and dysbiosis related to nutritional disorders. Hum Microbiome J 1:3-11.
• Tzeng A, Sangwan N, Jia M, Liu CC, Keslar KS, Downs-Kelly E, Fairchild RL, Al-Hilli Z, Grobmyer SR and Eng C (2021) Human breast microbiome correlates with prognostic features and immunological signatures in breast cancer. Genome Med 13:60.
• Urbaniak C, Cummins J, Brackstone M, Macklaim JM, Gloor GB, Baban CK, Scott L, O’Hanlon DM, Burton JP, Francis KP et al (2014) Microbiota of human breast tissue. App Environ Microbiol 80:3007-3014.
• Urbaniak C, Gloor GB, Brackstone M, Scott L, Tangney M and Reid G (2016) The microbiota of breast tissue and its association with breast cancer. Appl Environ Microbiol 82:5039-5048.
• Wang H, Altemus J, Niazi F, Green H, Calhoun BC, Sturgis C, Grobmyer SR and Eng C (2017) Breast tissue, oral and urinary microbiomes in breast cancer. Oncotarget 8:88122-88138.
• Wang H, Rong X, Zhao G, Zhou Y, Xiao Y, Ma D, Jin X, Wu Y, Yan Y, Yang H et al (2022) The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer. Cell Metab 34:581-594.e8.
• Wang Y, Xue J, Zhou X, You M, Du Q, Yang X, He J, Zou J, Cheng L, Li M et al (2014) Oral microbiota distinguishes acute lymphoblastic leukemia pediatric hosts from healthy populations. PLoS One 9:e102116.
• Wilkie T, Verma AK, Zhao H, Charan M, Ahirwar DK, Kant S, Pancholi V, Mishra S and Ganju RK (2022) Lipopolysaccharide from the commensal microbiota of the breast enhances cancer growth: Role of S100A7 and TLR4. Mol Oncol 16:1508-1522.
• Xuan C, Shamonki JM, Chung A, Dinome ML, Chung M, Sieling PA and Lee DJ (2014) Microbial dysbiosis is associated with human breast cancer. PLoS One 9:e83744.
• Zeisel SH and Warrier M (2017) Trimethylamine N-oxide, the microbiome, and heart and kidney disease. Annu Rev Nutr 37:157-181.
• Zhang J, Xie Q, Huo X, Liu Z, Da M, Yuan M, Zhao Y and Shen G (2022) Impact of intestinal dysbiosis on breast cancer metastasis and progression. Front Oncol 12:1037831.

Internet Resources

• World Health Organization - WHO, Breast cancer (2023) World Health Organization - WHO, Breast cancer (2023) https://www.who.int/es/news-room/fact-sheets/detail/breast-cancer/ (acessed 4 August 2023).
  » https://www.who.int/es/news-room/fact-sheets/detail/breast-cancer/
• National Cancer Institute(2023) Tumor markers in common use, National Cancer Institute(2023) Tumor markers in common use, https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-list/ (acessed 30 July 2023).
  » https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-list/

Edited by

Associate Editor:

Carlos F. M. Menck

Publication Dates

• Publication in this collection
  22 July 2024
• Date of issue
  2024

History

• Received
  03 Nov 2023
• Accepted
  10 May 2024