Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors

Abstract

Recent studies showed that changes to the gut microbiome alters the microbiome-derived metabolome, potentially promoting carcinogenesis in organs that are distal to the gut. In this study, we assessed the relationship between breast cancer and cadaverine biosynthesis. Cadaverine treatment of Balb/c female mice (500 nmol/kg p.o. q.d.) grafted with 4T1 breast cancer cells ameliorated the disease (lower mass and infiltration of the primary tumor, fewer metastases, and lower grade tumors). Cadaverine treatment of breast cancer cell lines corresponding to its serum reference range (100–800 nM) reverted endothelial-to-mesenchymal transition, inhibited cellular movement and invasion, moreover, rendered cells less stem cell-like through reducing mitochondrial oxidation. Trace amino acid receptors (TAARs), namely, TAAR1, TAAR8 and TAAR9 were instrumental in provoking the cadaverine-evoked effects. Early stage breast cancer patients, versus control women, had reduced abundance of the CadA and LdcC genes in fecal DNA, both responsible for bacterial cadaverine production. Moreover, we found low protein expression of E. coli LdcC in the feces of stage 1 breast cancer patients. In addition, higher expression of lysine decarboxylase resulted in a prolonged survival among early-stage breast cancer patients. Taken together, cadaverine production seems to be a regulator of early breast cancer.

Perturbation of the gut microbiota by antibiotics results in accelerated breast tumour growth and metabolic dysregulation

“…Administration of cadaverine to mice harbouring 4T1 BrCa tumours resulted in improved outcomes (smaller tumours, fewer metastases). Furthermore, cadaverine production was shown to be decreased in BrCa patients and correlated with survival [38]. To test this in our BrCa models we used fecal metabolomic analysis by NMR and observed significant metabolic dysregulation in the microbiota of VNMA treated animals ( Figure 4).…”

Microbiome and Breast Cancer: New Role for an Ancient Population

“…Some evidence shows that the microbiome metabolite influences the occurrence of BC; this hypothesis may help estimate the cancer risk and prevention. For instance, cadaverine as a biogenic amine is formed through the direct decarboxylation of L-lysine (45). It is reported that cadaverine biosynthesis is reduced in the gut in early-stage BC, resulting in lower production of an anti-cancer bacterial metabolite and reduced BC invasion (45).…”

“…For instance, cadaverine as a biogenic amine is formed through the direct decarboxylation of L-lysine (45). It is reported that cadaverine biosynthesis is reduced in the gut in early-stage BC, resulting in lower production of an anti-cancer bacterial metabolite and reduced BC invasion (45). It is shown that bacterial metabolites can stimulate oxidative and nitrosative stress that inhibit BC progression.…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…One of the best-characterized examples is microbiome-derived cadaverine, which ameliorates breast cancer by suppressing the proliferation, metastases, and aggressiveness of tumor cells, as well as epithelial-to-mesenchymal transition (EMT). 421 Cadaverine also initiates the metabolism of tumor cells that have shifted towards glycolysis by decreasing cellular oxygen consumption. 421 Additionally, microbial-derived LCA is significantly diminished 422 and is negatively correlated with the Ki-67 index in breast cancer.…”