Our study aimed at finding a mechanistic relationship between the gut microbiome and breast cancer. Breast cancer cells are not in direct contact with these microbes, but disease could be influenced by bacterial metabolites including secondary bile acids that are exclusively synthesized by the microbiome and known to enter the human circulation. In murine and bench experiments, a secondary bile acid, lithocholic acid (LCA) in concentrations corresponding to its tissue reference concentrations (< 1 μM), reduced cancer cell proliferation (by 10-20%) and VEGF production (by 37%), aggressiveness and metastatic potential of primary tumors through inducing mesenchymal-to-epithelial transition, increased antitumor immune response, OXPHOS and the TCA cycle. Part of these effects was due to activation of TGR5 by LCA. Early stage breast cancer patients, versus control women, had reduced serum LCA levels, reduced chenodeoxycholic acid to LCA ratio, and reduced abundance of the baiH (7α/β-hydroxysteroid dehydroxylase, the key enzyme in LCA generation) gene in fecal DNA, all suggesting reduced microbial generation of LCA in early breast cancer.

Objective-We investigated whether red cell infiltration of atheromatous lesions promotes the later stages of atherosclerosis. Methods and Results-We find that oxidation of ferro (FeII) hemoglobin in ruptured advanced lesions occurs generating ferri (FeIII) hemoglobin and via more extensive oxidation ferrylhemoglobin (FeIII/FeIVϭO). The protein oxidation marker dityrosine accumulates in complicated lesions, accompanied by the formation of cross-linked hemoglobin, a hallmark of ferrylhemoglobin. Exposure of normal red cells to lipids derived from atheromatous lesions causes hemolysis and oxidation of liberated hemoglobin. In the interactions between hemoglobin and atheroma lipids, hemoglobin and heme promote further lipid oxidation and subsequently endothelial reactions such as upregulation of heme oxygenase-1 and cytotoxicity to endothelium. Oxidative scission of heme leads to release of iron and a feed-forward process of iron-driven plaque lipid oxidation. The inhibition of heme release from globin by haptoglobin and sequestration of heme by hemopexin suppress hemoglobin-mediated oxidation of lipids of atheromatous lesions and attenuate endothelial cytotoxicity. Conclusion-The interior of advanced atheromatous lesions is a prooxidant environment in which erythrocytes lyse, hemoglobin is oxidized to ferri-and ferrylhemoglobin, and released heme and iron promote further oxidation of lipids. Oxysterols and oxidation products of polyunsaturated fatty acids are present in human atheromatous lesions. 4,5 Atherosclerotic lesions are hazardous regions for nucleated cells, both endothelial cells and, quite probably, incoming macrophages. 6 The major cytotoxic species may be oxidation products of lipids, particularly lipid hydroperoxides (LOOHs), aldehydes, and carbonyls. 6,7 In artificial systems, oxidation of polyunsaturated fatty acids requires reactive transition metals such as iron and copper. Based on our earlier work, 6,8,9 the metal in atheromatous lesions might be iron derived from heme. Nonprotein-bound heme is a particularly deleterious species inasmuch as it is hydrophobic and easily able to enter cell membranes. 10 In previous studies, we found that endothelial cells exposed to oxidized low-density lipoprotein (LDL) upregulated both heme oxygenase-1 (HO-1) and ferritin, 8,9 presumably as a defense mechanism. 6,11-14 Upregulation of HO-1 15 and ferritin H chain 16 in endothelial cells has been reported in the early phase of progression of atherosclerotic lesions. Expression of HO-1 provides protection against atherosclerosis in several experimental models, 17,18 and HO-1 deficiency in humans has been associated with the appearance of vasculature fatty streaks and atheromatous plaques at the age of 6. 19 We tested the hypothesis that heme-iron may accumulate in atherosclerotic lesions by intrusion and lysis of erythrocytes. Liberated hemoglobin is oxidized, and released hemeiron-dependent oxidation of lipids is strongly favored, contributing to further plaque development. Methods Tissue SamplesSpecimens of ...

Breast cancer is a leading cause of death among women worldwide. Dysbiosis, an aberrant composition of the microbiome, characterizes breast cancer. In this review we discuss the changes to the metabolism of breast cancer cells, as well as the composition of the breast and gut microbiome in breast cancer. The role of the breast microbiome in breast cancer is unresolved, nevertheless it seems that the gut microbiome does have a role in the pathology of the disease. The gut microbiome secretes bioactive metabolites (reactivated estrogens, short chain fatty acids, amino acid metabolites, or secondary bile acids) that modulate breast cancer. We highlight the bacterial species or taxonomical units that generate these metabolites, we show their mode of action, and discuss how the metabolites affect mitochondrial metabolism and other molecular events in breast cancer. These metabolites resemble human hormones, as they are produced in a “gland” (in this case, the microbiome) and they are subsequently transferred to distant sites of action through the circulation. These metabolites appear to be important constituents of the tumor microenvironment. Finally, we discuss how bacterial dysbiosis interferes with breast cancer treatment through interfering with chemotherapeutic drug metabolism and availability.