The Gut Microbiome: A New Player in Breast Cancer Metastasis

In breast cancer patients, the diversity of the microbiome decreases, coinciding with decreased production of cytostatic bacterial metabolites like lithocholic acid (LCA). We hypothesized that LCA can modulate oxidative stress to exert cytostatic effects in breast cancer cells. Treatment of breast cancer cells with LCA decreased nuclear factor-2 (NRF2) expression and increased Kelch-like ECH associating protein 1 (KEAP1) expression via activation of Takeda G-protein coupled receptor (TGR5) and constitutive androstane receptor (CAR). Altered NRF2 and KEAP1 expression subsequently led to decreased expression of glutathione peroxidase 3 (GPX3), an antioxidant enzyme, and increased expression of inducible nitric oxide synthase (iNOS). The imbalance between the pro- and antioxidant enzymes increased cytostatic effects via increased levels of lipid and protein oxidation. These effects were reversed by the pharmacological induction of NRF2 with RA839, tBHQ, or by thiol antioxidants. The expression of key components of the LCA-elicited cytostatic pathway (iNOS and 4HNE) gradually decreased as the breast cancer stage advanced. The level of lipid peroxidation in tumors negatively correlated with the mitotic index. The overexpression of iNOS, nNOS, CAR, KEAP1, NOX4, and TGR5 or the downregulation of NRF2 correlated with better survival in breast cancer patients, except for triple negative cases. Taken together, LCA, a metabolite of the gut microbiome, elicits oxidative stress that slows down the proliferation of breast cancer cells. The LCA–oxidative stress protective pathway is lost as breast cancer progresses, and the loss correlates with poor prognosis.

Section: Resultssupporting

confidence: 69%

Lithocholic Acid, a Metabolite of the Microbiome, Increases Oxidative Stress in Breast Cancer

Kovács

Csonka

Kovàcs

et al. 2019

“…We assessed whether IS can modulate cancer hallmarks that were modulated by other cytostatic bacterial metabolites [ 16 , 17 , 41 , 47 , 61 , 62 , 63 , 64 , 65 ]. First, we assessed oxidative/nitrosative stress markers, as these are major regulators of cancer hallmarks and cancer progression [ 66 , 67 , 68 , 69 , 70 ].…”

Section: Resultsmentioning

confidence: 99%

“…The underlying molecular mechanism involved in IS effects on tumor progression is the reversal of the epithelial-to-mesenchymal transition, similar to other metabolites [ 16 , 17 , 40 , 41 , 44 , 45 , 47 ]. Reverting or inhibiting EMT slows cell movement, diapedesis, and metastasis formation, as was observed in our study.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, oncobiosis supports epithelial-to-mesenchymal transition (EMT) [ 16 , 17 , 40 , 44 ], migration and invasion [ 17 , 40 ], the reduction of oxidative stress [ 40 , 45 ], the proportions of ALDH1+ cancer stem cells [ 17 , 40 ], and widespread metabolic alterations [ 16 , 17 , 40 ] in cancers cells. These elementary steps are translated into enhanced tumor growth [ 16 , 17 ], aggressive tumor infiltration to the surrounding tissues [ 16 , 17 ], and enhanced metastasis formation [ 16 , 17 , 41 , 46 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Indoxylsulfate, a Metabolite of the Microbiome, Has Cytostatic Effects in Breast Cancer via Activation of AHR and PXR Receptors and Induction of Oxidative Stress

Sári

Mikó

Kovàcs

et al. 2020

Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.

“…Bacterial metabolites modulate the redox balance of cancer cells [24,34], as well as cancer cell metabolism [22,23]. These processes culminate in cytostasis, a reprogramming of the epithelial-mesenchymal transition leading to decreased cancer stem cells [22][23][24][25]29,34,35,45]. These basic events are the pillars for the inhibition of cancer cell growth, movement, and metastasis formation [46][47][48].…”

Section: Pancreatic Adenocarcinoma An Unmet Medical Needmentioning

confidence: 99%

Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma

Kiss

Mikó

Sebő³

et al. 2020

Pancreatic adenocarcinoma is one of the most lethal cancers in both men and women, with a median five-year survival of around 5%. Therefore, pancreatic adenocarcinoma represents an unmet medical need. Neoplastic diseases, such as pancreatic adenocarcinoma, often are associated with microbiome dysbiosis, termed oncobiosis. In pancreatic adenocarcinoma, the oral, duodenal, ductal, and fecal microbiome become dysbiotic. Furthermore, the pancreas frequently becomes colonized (by Helicobacter pylori and Malassezia, among others). The oncobiomes from long- and short-term survivors of pancreatic adenocarcinoma are different and transplantation of the microbiome from long-term survivors into animal models of pancreatic adenocarcinoma prolongs survival. The oncobiome in pancreatic adenocarcinoma modulates the inflammatory processes that drive carcinogenesis. In this review, we point out that bacterial metabolites (short chain fatty acids, secondary bile acids, polyamines, indole-derivatives, etc.) also have a role in the microbiome-driven pathogenesis of pancreatic adenocarcinoma. Finally, we show that bacterial metabolism and the bacterial metabolome is largely dysregulated in pancreatic adenocarcinoma. The pathogenic role of additional metabolites and metabolic pathways will be identified in the near future, widening the scope of this therapeutically and diagnostically exploitable pathogenic pathway in pancreatic adenocarcinoma.