Complicated etiology reveals beneath the BC. Although the exact biological events of BC are unclear, it is well established that endogenous estrogen is a significant risk factor in BC. Over 70% of BC patients have estrogen receptor-positive subtypes (Kwa et al., 2016). Estrogen metabolism is influenced by the variety of the intestinal microbiota, which is involved in controlling estrogen levels. One of the potential GM pathways influencing BC is the estrogen pathway. The steady decrease in C-27 cholesterol results in the production of estrogen, a steroid hormone. The primary forms of endogenous estrogen are estradiol, estrone, and estriol. Endogenous estrogens typically circulate in the bloodstream in free or protein-bound form to exert their biological effects. GM regulates the levels of circulating estrogens and influences the risk of hormone-driven malignancies through direct or indirect effects. The higher free estrogen levels in the gut can impact the relative plasma levels of estrogens and metabolites, increasing the risk of cancer progression (Figure 1; Kwa et al., 2016). Mani (2017) studied the relationship between endogenous estrogens, intestinal microbiota, and BC. They reported that ovaries, adrenal glands, adipose, and other tissues make up the total amount of estrogen in the body.

Meanwhile, the liver is the leading site for metabolite formation, binding, and unbinding. Notably, microbial enzymes in the gut participate in the dissociation of estrogen, regulating the recirculation and total estrogen levels. Various circulatory metabolites impact the growth and development of estrogen receptor-positive BC (Figure 2; Mani, 2017). Parida and Sharma (2019) pointed out that endogenous estrogen is the main causative factor of BC in menopausal women. Before menopause, the ovary is the leading site of estrogen synthesis, and circulating estrogen acts in an endocrine manner on multiple targets. However, after menopause, estrogen production depends on the adipose tissue, bone, and the brain, serving in paracrine and endocrine manners. The microorganisms capable of metabolizing estrogen in the gastrointestinal tract were named “estrogenome (C-18 steroid hormones, estrogen E1, estrogen E2, estrogen E3).” The members of “estrogenome” regulate endogenous estrogen metabolism through β-glucuronidase and β-glucosidase activities via the hepatic-intestinal cycle to maintain estrogen homeostasis. The intestinal microbiota determines the excretion and recirculation of endogenous estrogens in postmenopausal women (Figure 3; Parida and Sharma, 2019).

The intestinal immune system is an essential component of the human immune system, and the dysregulation of intestinal microbiota can impair the immune response, inducing various diseases, including extra-intestinal cancers. Rao et al. (2006) explored the role of Helicobacter hepaticus, an intestinal bacterial pathogen, in the induction of mammary carcinogenesis in C57BL/6 Apc Min/ + female mice. They found that H. hepaticus promoted mammary carcinogenesis through a tumor necrosis factor α-dependent (TNFα) mechanism, promoting epithelial tumorigenesis locally and at distant sites such as mammary glands (Rao et al., 2006). Immune dysregulation, which often originates from infection of the intestinal microbiota, is one of the causes of BC development. The mucosal surface of the intestines harbors a diverse population of microflora. During chronic infection by pathogenic gastrointestinal bacteria, the integrity of the intestinal epithelial barrier is compromised. This damage allows the bacteria to translocate from the intestine lumen to the underlying mucosal tissue (Rao et al., 2007).

Consequently, immune-inflammatory response cells become continuously activated, producing excess inflammatory cytokines. This dysregulation of immune activity involving persistent inflammation contributes to tumor formation (Rao et al., 2007). Loman et al. (2022) conducted a study investigating the correlation between BC and GM, utilizing samples obtained from mammary tumors in mice. It has been found that BCs generate pro-inflammatory cytokines, resulting in the compromise of intestinal barrier integrity. This phenomenon facilitates the translocation of intestinal bacteria and triggers systemic inflammation, leading to the manifestation of gastrointestinal and behavioral problems. In general, this procedure worsened the state of BC in mice (Loman et al., 2022).

Zhang et al. (2023) used an intestinal epithelial VDR knockout mouse model of BC to investigate the effects of vitamin D deficiency. The researchers discovered that a shortage in vitamin D resulted in an elevation of intestinal permeability, compromising the structural integrity of tight junctions within the intestines. Consequently, this phenomenon led to modifications in the composition of the intestinal microbiota, thereby facilitating the proliferation of BCs in terms of quantity and dimensions. Significantly, the findings of their study emphasized the interrelation among the gastrointestinal tract, mammary glands, and microbiome, indicating that preserving the intestinal barrier’s integrity might contribute to the onset of tumors outside the gastrointestinal system. Additional investigations can delve into preventative and therapeutic methodologies for extra-intestinal diseases like BC (Zhang et al., 2023).

Lakritz et al. (2015) reported that neutrophils are one of the primary immune factors in GM affecting BC development and progression. Neutrophils can induce genotoxic damage by producing reactive oxygen species, resulting in an initial mutagenic event of carcinogenesis.

In contrast, cytokines and chemokines secreted by tumor-associated neutrophils can shape the tumor microenvironment, contributing to tumor growth. Studies have demonstrated that GMs that face challenges can increase the activity of inflammatory cells in breast tissue. Conversely, the reduction of neutrophils throughout the body has been found to impede the establishment of breast tumors. Additionally, it has been demonstrated that the inflammatory response of GM has a role in the advancement of parenteral cancer by affecting neutrophil-mediated mechanisms (Lakritz et al., 2015).

Intestinal microbial metabolites, such as amino acids, short-chain fatty acids, and hypocholesterolemic acid, are also involved in BC progression. The metabolic pathway exhibits immunoregulatory properties in BC. The GM can convert tryptophan found in the food into several indole derivatives. These derivatives serve as ligands for the aromatic hydrocarbon receptor pathway, an immunomodulator of the gastrointestinal tract. The upregulation of the aromatic hydrocarbon receptor can amplify tryptophan metabolism-inducing BC cells, leading to apoptosis (Bekki et al., 2015). Cadaverine, a product of bacterial decarboxylation of lysine and arginine, contributes to lower gut pH, affecting bacterial growth. Relative to healthy individuals, BC individuals had a lower abundance of Enterobacteriaceae CadA as well as E. coli, Enterobacter cloacae, and Hafnia LDC DNA, and the microbiota as mentioned above were primarily responsible for bacterial cadaverine production, resulting in significantly lower levels of cadaverine in BC individuals than in healthy individuals. Cadaverine can induce mesenchyme transformation into epithelial cells via the TAAR receptor in vitro and in vivo. It exhibits a reduction in tumor infiltration into peripheral organs and effectively manages the occurrence of distant metastasis.

Furthermore, the compound known as cadaverine has demonstrated significant efficacy in suppressing the proliferation, migration, invasion, and stem cell characteristics of BC cells. It is worth noting that during the initial phase of BC, there is a notable decrease in the synthesis of cadaverine within the human body. A correlation exists between diminished levels of cadaverine production and a reduction in the diversity of gut bacteria populations (Kovács T. et al., 2019).

Short-chain fatty acids (SCFAs), Including butyric, propionic, and acetic acids, are the most studied gut microbial metabolites. SCFAs are produced in the small intestine and are important microbial messengers of the immune system. SCFAs are involved in complex host-microbiome interactions and intestinal immune responses. They exert anti-inflammatory effects and enhance microbial pathogen tolerance by inhibiting histone deacetylase and activating anti-inflammatory cytokines produced by GPR109A and GPR43. SCFAs play a positive influence on intestinal homeostasis as well as on the immune-metabolic function of the body (Figure 4; Aarnoutse et al., 2022). The study by Yoon et al. (2019) evaluated the association between the physiological intestinal absorption of BC patients and their intestinal bacteria composition. According to the research, the Ruminalococcaceae family has been found to have a preference for the generation of butyric acid, which serves as a crucial microbial regulator of immunological function inside the intestinal mucosa. Consequently, this family can serve as a sign of a well-functioning anaerobic intestinal microbiota.

Moreover, the abundance of butyrate-producing bacteria decreases in the GM of BC patients, significantly correlating with mucosal destruction and increased mucosal inflammation in BC (Yoon et al., 2019). Butyrate is transported into cells by the SMCTI transporters and distributed throughout the body by other transporter proteins, resulting in a systemic impact. The excessive buildup of intracellular butyrate can potentially contribute to the onset and progression of malignant diseases. In the context of BC, it has been observed that butyrate can restrict the proliferation of BC cells. This effect is achieved through its role as an inhibitor of histone deacetylase (HDACi), which stimulates the production of p21. This kinase inhibitor operates inside the cytosol and depends on cytosolic proteins (Mirzaei et al., 2021).

A study noted significant changes in the composition and symbiosis of the intestinal microbiota in pre-menopausal BC patients relative to healthy pre-menopausal women. The BC patients showed a substantial reduction in the abundance of SCFA-producing bacteria and related enzymes. Compared with normal breast cells, propionate and butyrate reduce the activity of BC cells in a dose-dependent manner. This again highlights that SCFAs can help slow down the progression of BC, mainly through regulating immune function and inflammatory factors, such as T-cell and histone deacetylase activities (He et al., 2021).

Bile acids are soluble derivatives of cholesterol produced in the liver that are converted by gut microbes to form a variety of metabolites. In the gut, a portion of bile acids are converted by gut bacteria into secondary bile acids, which are retained in the circulation and mediate receptor-mediated effects on cancer cells through the extracellular signal-regulated kinases ERK and PKC, which induce DNA binding and trans-activation of activator protein 1 (AP-1). Secondary bile acids were recognized as a liver and colon cancer risk factor. Lithocholic acid, a type of secondary bile acid, was shown to inhibit the proliferation and invasion of BC cells through TGR5 (Mikó et al., 2018). In the early stages of BC, the diversity of the gut microbiome decreases, along with the production of inhibitory bacterial metabolites such as lithocholic acid. The expression of key components in the secondary bile acid-induced cytostatic pathway (iNOS and 4HNE) decreases with the progress of BC. Lipid peroxidation levels in tumors negatively correlate with mitotic index. In triple-negative cases, overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or downregulation of NRF2 was related to improved BC patient survival. Secondary bile acids cause oxidative stress, which slows BC cell proliferation (Kovács P. et al., 2019). Sodium bile deoxycholate (SBDC), synthesized by intestinal bacteria, facilitates the processing of host dietary fats. Also, SBDC was shown to reduce the crude apoptotic neuro-adenocarcinoma levels and promote the growth of tumor cells by upregulating Flk-1 (Krishnamurthy et al., 2008; Franco, 2022).

Bacteria are an essential component of tumors and are found in the cytoplasm of immune and tumor cells. Various intracellular bacteria in BC tissues have been confirmed to play a vital role in the metastasis of BC (Fu et al., 2022). Parida et al. (2021) reported that Bacteroides fragilis is a common colonizing bacterium that asymptomatically lives in individuals, and its virulence is attributed to zinc metalloproteinase toxins. B. fragilis can influence the structure of the gut microbial community based on its secretion products and is a significant factor in diarrhea, inflammatory bowel disease, and carcinomatous transformation of the intestinal mucosa. B. fragilis toxins can promote tumor growth and metastasis in BC through intestinal and intraductal colonization via the β-catenin and Notch1 pathways (Parida et al., 2021). Alterations in intestinal microbiota play a key role in tumor development and suppression (Kondegowda et al., 2011). Microbial peptides from intracellular bacteria can remodel the tumor microenvironment (TIME) by providing targets for CTL and CD4+ T cells under the presentation of MHC class I or II molecules on the surface of tumor cells (Terrisse et al., 2023). For instance, H. hepaticus is a pathogen found in mice’s liver and intestines. In mammary tumor-prone mice, H. hepaticus intestinalis was shown to promote mammary and intestinal tumors. Furthermore, the commensal bacteria in the tract metastasize to distant organs and promote cancer progression. H. hepaticus-induced dysbiosis of the intestinal microbiota promoted the systemic spread of bacteria. Intestinal bacterial subpopulations can move from the gut to the breast via the lymph nodes and establish a pro-inflammatory microenvironment (Deng et al., 2022).