Increasingly, cancer researchers are looking beyond tumor cells themselves to understand what drives malignancy. A growing body of work suggests that microbes—once thought irrelevant to breast tissue—may shape tumor behavior in powerful ways.
In a new study published in Cancer Research, investigators led by Dipali Sharma, PhD, at the Johns Hopkins Kimmel Cancer Center, report that several pathogenic bacteria can accelerate breast cancer progression by converging on a single metabolic enzyme: spermine oxidase (SMOX), a key regulator of polyamine metabolism.
The findings identify what Sharma describes as a shared molecular pathway used by distinct pathogens to promote tumor growth—and point to SMOX inhibition as a potential therapeutic strategy.
A rapidly evolving field
For decades, breast tissue was widely considered sterile. That view has shifted.
“I think this whole field, I would start from a couple of years ago,” Sharma said in an interview. “Five, ten years ago, when the microbiota field was booming, then we were all thinking about microbiota, its association with different diseases.”
While microbial influences have long been studied in colon cancer, only recently have researchers demonstrated microbial signatures in freshly collected breast tumor samples. In 2021, Sharma’s group previously reported that gut-associated pathogens can influence breast cancer progression, providing early mechanistic evidence that microbes outside the breast may still shape its disease biology.
“So microbiota influence on various cancers has been shown,” she said, “but most studies have focused on gut-related illness like colon cancer.” Work in breast cancer, she added, “is a rapidly evolving field. Yes, it’s relatively new.”
Converging on the polyamine pathway
In their earlier work, Sharma’s team showed that a colon-associated microbe linked to colorectal cancer could also impact breast tumor progression. In the new study, they asked a broader question: If multiple bacteria are present in breast tumors, might they rely on a common pathway to exert their effects?
“We started with a question that, if we have these multiple bacteria in the breast, are they using a common pathway by chance?” Sharma explained. “So we found that multiple bacteria are using the one—they’re kind of converging on this one pathway. So if we can inhibit this one pathway, we can inhibit the effect of multiple bacteria.”
That pathway is polyamine metabolism.
“Cancer cells are addicted to the polyamine pathway,” Sharma said. “So they will generate their own polyamines, and they will also get polyamines from the cancer microenvironment.”
At the center of this metabolic axis is spermine oxidase. “Spermine oxidase is an enzyme that keeps the polyamine levels, maintains the polyamine levels in the cell,” she said. “SMOX is a key enzyme that we can inhibit.”
By exposing breast cancer cells and mouse mammary tissue to pathogenic bacteria—including enterotoxigenic Bacteroides fragilis (ETBF)—the researchers observed increased SMOX activity, oxidative stress, and DNA damage. The bacteria also triggered a rise in inflammatory cytokines interleukin-6 (IL6) and tumor necrosis factor-alpha (TNFα), both of which further amplified SMOX expression and activity. They also showed that other pathogens, including toxin-producing E. coli and F. nucleatum, had similar effects, suggesting a shared metabolic vulnerability.
Modeling infection-driven tumor growth
To test the functional impact of infection, Sharma’s team used mouse models. Healthy mice were given oral bacterial infections and then assessed to determine whether the microbes could reach mammary tissue.
“Healthy mice will be given bacterial infection, oral infection, and then we would look at the mammary tissue, if the bacteria is actually reaching the mammary tissue,” Sharma said.
In tumor-bearing mice infected with bacteria, the investigators administered SMOX inhibitors to evaluate whether blocking polyamine metabolism could counteract bacteria-driven tumor growth.
The results were striking: SMOX inhibition reduced tumor burden and mitigated bacterial effects on cancer progression in preclinical models.
By targeting a host enzyme rather than the microbes themselves, the strategy may offer a way to blunt tumor-promoting inflammation and oxidative DNA injury triggered by dysbiosis.
Local and distant effects of pathogens
Sharma emphasized that microbes may influence breast cancer through both local colonization and distant signaling.
“If people have this bacteria—B. fragilis or F. nucleatum—multiple pathogenic bacteria which might be present in the oral cavity or in the gut, they release these toxins which can affect the cells two ways,” she said. “One, the bacteria can be present in the breast tissue itself. Second, it can be present in the oral cavity or in the gut, and they release these toxins, and that’s how they can have these local and also the far-reaching effects.”
In a separate recent study, her group showed that an oral pathogen associated with periodontal disease could be traced to mammary tissue in mice. “These healthy mice develop hyperplasia in two weeks,” she said—lesions resembling early precursors of ductal carcinoma in situ.
Such findings raise questions about how infection and inflammation intersect with established breast cancer risk factors.
“As we all appreciate, it’s a multifactorial disease,” Sharma said. “It’s not just one factor that will be a causative agent. It might be multiple factors coming together.”
She suggested that microbial exposure may be particularly consequential in high-risk populations—such as individuals with inherited mutations, strong family histories, or preexisting breast lesions.
“If they have another risk factor—for example, if they have some mutations that their cells are already on the crux of developing a cancer—then having this kind of infection from a pathogen might actually tip the balance toward cancer development,” she said.
Clinical implications and next steps
The new findings suggest that SMOX activity—or microbial composition—could eventually serve as biomarkers of aggressive disease. More immediately, they raise the possibility of combining SMOX inhibitors with standard therapies in selected patients.
Sharma also hopes the work encourages awareness among clinicians and patients.
“I just feel that if people take more care—if they have gut-related diseases, and if they’re at high risk of developing breast cancer, and if they happen to have periodontal disease—I just like people to know so they can be more aware of it,” she said. “They can discuss this with their physicians
