Spermine Oxidase Serves as a Key Functional Node in Microbial Dysbiosis–Induced Breast Carcinogenesis

Emerging evidence has highlighted the unequivocal importance of microbiota as a risk factor for breast carcinogenesis. Elucidating the underlying mechanisms is needed to identify key nodes that can be inhibited to abolish pathogenic microbe-mediated breast cancer growth and metastatic progression. Focusing on a procarcinogenic colon microbe, enterotoxigenic Bacteroides fragilis (ETBF), we uncovered the involvement of spermine oxidase (SMOX), a key enzyme of polyamine metabolism, in promoting breast tumorigenesis. Interestingly, exposure of breast cancer cells to multiple pathogenic microbes, such as Fusobacterium nucleatum and pks+Escherichia coli, and to bacterial toxins induced SMOX expression, whereas nonpathogenic bacteria exhibited no impact. Elevated levels of proinflammatory cytokines IL6 and TNFα were observed in cells exposed to multiple pathogenic bacteria, and both of these cytokines were capable of upregulating SMOX expression and activity. ETBF and B. fragilis toxin exposure led to a considerable increase in reactive oxygen species activity, induction of γH2AX foci formation, and altered expression of major DNA damage response (DDR) proteins, which were abrogated with SMOX inhibition. Pharmacologic inhibition of SMOX using MDL72527 and SXG-1 effectively impeded ETBF-induced breast carcinogenesis with long-lasting effects on tumor-dissociated cells. This work implicates the IL6/TNFα-SMOX-DDR axis as a functional mediator of the oncogenic effects of pathogenic bacteria and proposes SMOX inhibitors as an intervention strategy for treating patients with breast cancer with microbial dysbiosis. SIGNIFICANCE: Overabundance of opportunistic pathogens elevates SMOX activity via proinflammatory cytokines to accelerate breast cancer progression, which can be targeted with pharmacological inhibitors of SMOX to significantly inhibit microbiota-associated carcinogenesis.