Johns Hopkins scientists have traced how certain bacteria in the gut and breast tissue can push breast cancer to grow and spread by hijacking a single enzyme. Their findings spotlight a new drug target that could help protect patients whose microbiomes are out of balance.
Researchers at the Johns Hopkins Kimmel Cancer Center have uncovered a molecular chain reaction that helps explain how certain bacteria in the gut and breast tissue can push breast cancer to grow and spread — and how a single enzyme might be used to stop them.
The team found that several pathogenic, or disease-causing, bacteria can hijack a metabolic enzyme called spermine oxidase, or SMOX, to damage DNA, fuel tumor growth and promote metastasis in laboratory and animal models of breast cancer. Blocking that enzyme sharply reduced tumor formation, even when harmful microbes were present.
The work, published Feb. 15 in the journal Cancer Research, adds breast cancer to a growing list of cancers that appear to be influenced by the microbiome — the vast community of bacteria and other microbes that live in and on the human body.
“Microbes don’t just reside in our gut. They can directly influence cancer behavior,” Dipali Sharma, a professor of oncology and a Fetting Fund scholar who led the research, said in a news release. “We found that an overabundance of certain pathogenic bacteria triggers inflammation and activates SMOX, producing reactive oxygen species that damage DNA and fuel tumor growth. By blocking SMOX, we were able to dramatically reduce tumor formation in our preclinical models.”
The researchers focused first on enterotoxigenic Bacteroides fragilis, or ETBF, a strain known to secrete a powerful toxin that can reshape microbial communities and promote cancer in other organs. When breast cancer cells or mouse mammary tissue were exposed to ETBF or its toxin, SMOX levels surged.
That spike in SMOX set off a cascade: increased oxidative stress, heightened inflammation and greater genomic instability — all conditions that make it easier for tumors to form and become more aggressive.
The team then asked whether this effect was unique to ETBF. In further experiments, they found that other pathogenic microbes, including Fusobacterium nucleatum and toxin-producing Escherichia coli, had similar impacts on SMOX and DNA damage. Nonpathogenic, or harmless, bacteria did not trigger the same response.
The bacteria also drove up levels of inflammatory signaling molecules called cytokines, specifically interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα). Those cytokines, in turn, further boosted SMOX activity.
“This establishes a self-perpetuating loop,” added first author Deeptashree Nandi, a postdoctoral fellow in Sharma’s lab. “Inflammatory cytokines stimulate SMOX, SMOX generates oxidative stress, and the resulting DNA damage helps tumors grow and spread.”
To see if they could break that loop, the researchers treated breast cancer cells and mouse models with two SMOX-blocking compounds, MDL72527 and SXG-1. Both drugs effectively suppressed SMOX activity, reduced markers of DNA damage and halted tumor progression, even when pathogenic bacteria were present.
In mice colonized with ETBF, mammary tumors appeared more often and grew faster than in uninfected animals. But when those colonized mice received SMOX inhibitors, they developed much smaller tumors, had fewer metastases and showed lower signs of oxidative DNA injury.
The results point to a promising new way to protect patients whose microbiomes are out of balance, a condition known as microbial dysbiosis, according to Sharma.
“These findings suggest that pharmacologic inhibition of SMOX could be a viable strategy to counteract the cancer-promoting effects of microbial dysbiosis,” she said.
The researchers also tested whether the SMOX-driven pathway extended beyond the initial bacteria they studied. They found that pathogenic Fusobacterium nucleatum, E. coli and even culture extracts from Mycobacterium tuberculosis all induced SMOX upregulation and DNA damage in breast cancer cells.
“This convergence across distinct bacterial species suggests that SMOX may represent a shared molecular hub through which microbes influence cancer biology,” Sharma added.
That shared hub could make SMOX a particularly attractive drug target, because it might allow doctors to blunt the cancer-promoting effects of multiple harmful microbes without needing to eliminate each one individually.
Beyond treatment, the findings hint at new possibilities for risk assessment and prevention. Measuring SMOX activity or profiling the microbial communities in the gut and breast tissue could one day help identify women who are more likely to develop aggressive disease.
The team is now exploring SMOX inhibitors as potential add-ons to standard breast cancer therapies and studying how microbe-driven inflammation shapes the immune system’s response to tumors. Understanding those interactions could help researchers design combination treatments that both attack cancer cells directly and neutralize the microbial signals that help tumors thrive.
“Understanding how bacteria communicate with cancer cells opens entirely new avenues for prevention and treatment,” added Sharma. “If we can interrupt that conversation — particularly by targeting SMOX — we may be able to slow or even stop cancer progression in patients affected by microbial imbalance.”
While the work is still in preclinical stages and will require extensive testing before any SMOX-targeting drugs reach patients, it underscores a broader shift in cancer research: looking beyond tumor cells themselves to the ecosystems of microbes, immune cells and chemical signals that surround them.
For students and early-career scientists, the study offers a vivid example of how basic biology — in this case, an enzyme involved in processing a common cellular molecule — can become a bridge between microbiology and oncology, and potentially between lab bench and bedside.
Source: Johns Hopkins Medicine