Fecal expression of Escherichia coli lysine decarboxylase (LdcC) is downregulated in E-cadherin negative lobular breast carcinoma

et al. 2020

Cancers

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Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome’s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.

“…The average stage and grade were not statistically different amongst the groups. The cohort was published in [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Bacteriodes Xylanisolvensmentioning

confidence: 99%

Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress

Sári

Mikó

et al. 2020

Cancers

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“…Multiple microbial compartments undergo oncobiotic transformation during breast cancer, including breast tissue [55,56], milk ducts [57], the inherent microbiome of the breast carcinoma [54,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72], the distal gut [51,52,[73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89], and the urinary microbiome [54,90]. However, no differences in the microbiome of the nipple [57,69] and the oral microbiome [54] between healthy individuals and breast cancer patients have been detected.…”

Section: Oncobiosis In Breast Cancermentioning

confidence: 99%

“…The gut microbiome undergoes oncobiotic transformation in breast cancer [21,51,52,[73][74][75][76][77][78][79][80][81][82]. In terms of diversity indices, Goedert and colleagues [73] and Byrd and colleagues [74] reported lower or trends towards lower diversity indices in three different cohorts, while Zhu and colleagues [75] and Bobin-Dubigeon and co-workers [84] reported increased alpha diversity indices.…”

Section: Bacterial Metabolite Signaling and The Oncobiosis Of The Gastrointestinal Tract And Urinary Tractmentioning

confidence: 99%

“…High total body fat was associated with lower Chao1 and OTU indices [ 51 ] 48 postmenopausal BC case patients (most stages 0–I), vs 48 control patients (same as [ 73 ]) qPCR of specific loci Abundance of DNA coding for the baiH gene of Clostridium sordelli , Bacteroides thetaiotaomicron , Escherichia coli , Pseudomonas putida , and Staphylococcus haemolyticus decreased in breast cancer patients, the most pronounced changes were detected in in situ carcinoma patients [ 78 ] 48 postmenopausal BC case patients (most stages 0–I), vs 48 control patients (same as [ 73 ]) qPCR of specific loci Abundance of DNA coding for the CadA gene of Escherichia coli and the LdcC gene of Escherichia coli , Enterobacter cloacae , and Hafnia alvei decreased in breast cancer patients, the most pronounced changes were detected in in situ carcinoma patients [ 79 ] 3 control and 4 stage I BC patients Western blotting Fecal expression of Escherichia coli LdcC protein was lower in stage I patients 48 postmenopausal BC case patients (most stages 0–I), vs 48 control patients (same as [ 73 ]) qPCR of specific loci Abundance of DNA coding for the TnaA gene of Alistipes shahii , Providencia rettegri , Bacteroides xylanisolvens , and Clostridium sp. decreased in breast cancer patients, the most pronounced changes were detected in in situ carcinoma patients [ 80 ] 35 BC patients Western blotting Fecal expression of Escherichia coli TnaA was higher in patients with tumor-infiltrating lymphocyte (TIL) ratio over 20% compared to that of those below. Fecal E. coli TnaA expression correlated with TIL percentage 35 BC cases Western blotting Fecal expression of TnaA Escherichia coli LdcC protein was lower in lobular cases [ 81 ] 48 postmenopausal BC cases, 48 control 16S rRNA gene sequencing Lower alpha diversity in breast cancer patients.…”

Section: Oncobiosis In Breast Cancermentioning

confidence: 99%

See 1 more Smart Citation

The involvement of oncobiosis and bacterial metabolite signaling in metastasis formation in breast cancer

Mikó

Ujlaki

et al. 2021

Cancer Metastasis Rev

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Breast cancer, the most frequent cancer in women, is characterized by pathological changes to the microbiome of breast tissue, the tumor, the gut, and the urinary tract. Changes to the microbiome are determined by the stage, grade, origin (NST/lobular), and receptor status of the tumor. This year is the 50th anniversary of when Hill and colleagues first showed that changes to the gut microbiome can support breast cancer growth, namely that the oncobiome can reactivate excreted estrogens. The currently available human and murine data suggest that oncobiosis is not a cause of breast cancer, but can support its growth. Furthermore, preexisting dysbiosis and the predisposition to cancer are transplantable. The breast’s and breast cancer’s inherent microbiome and the gut microbiome promote breast cancer growth by reactivating estrogens, rearranging cancer cell metabolism, bringing about a more inflammatory microenvironment, and reducing the number of tumor-infiltrating lymphocytes. Furthermore, the gut microbiome can produce cytostatic metabolites, the production of which decreases or blunts breast cancer. The role of oncobiosis in the urinary tract is largely uncharted. Oncobiosis in breast cancer supports invasion, metastasis, and recurrence by supporting cellular movement, epithelial-to-mesenchymal transition, cancer stem cell function, and diapedesis. Finally, the oncobiome can modify the pharmacokinetics of chemotherapeutic drugs. The microbiome provides novel leverage on breast cancer that should be exploited for better management of the disease.

The role of bile acids in carcinogenesis

Režen

Rozman

et al. 2022

Cell. Mol. Life Sci.

Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.