Oral bacterium may promote breast cancer development and spread

Researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy found that an oral bacterium commonly associated with periodontal disease can promote breast cancer initiation, tumor growth and spread by inducing DNA damage and altering cancer cell behavior.

The study, published Jan. 15 in Cell Communication and Signaling, shows that Fusobacterium nucleatum, an oral microbe previously linked to colorectal and other cancers, can travel through the bloodstream and colonize in breast tissue, where it causes inflammation and other precancerous changes. The researchers, led by Dipali Sharma, Ph.D., professor of oncology and a John Fetting Fund for Breast Cancer Prevention investigator, found that the bacterium accelerated tumor growth and increased the spread of cancer cells from the breast to the lung in animal models of human breast cancer.

“The key takeaway is that this oral microbe can reside in breast tissue and that there is a connection between this pathogen and breast cancer,” says Sharma, adding that the team’s study was inspired by many small studies that looked at thousands of patients and connected periodontal disease to breast cancer.

“We wanted to dig deeper and see if we could uncover the underlying connections,” says Sheetal Parida, Ph.D., first author and a research associate working with Sharma.

Using mouse models and human breast cancer cells, Sharma and team found that intraductal exposure to F. nucleatum led to the formation of metaplastic and hyperplastic lesions — noncancerous changes where cells either multiply too much or transform into a different kind of cell — in breast tissue, accompanied by inflammation, DNA damage and increased cell growth. When introduced into the bloodstream, the bacterium significantly accelerated the growth and spread of established breast tumors.

The researchers also identified a molecular mechanism underlying these effects. Exposure to F. nucleatum caused DNA damage to cells and activated repair pathways that can introduce mistakes, including nonhomologous end joining, a fast but error-prone way that cells repair broken DNA by directly connecting the broken ends back together. The researchers found that even brief exposure to the bacterium initiated increased expression of a protein called PKcs that was associated with enhanced tumor cell migration, invasion, stem-like behavior and resistance to chemotherapy.

The researchers also found that epithelial cells (the cells that line the breast ducts) and breast cancer cells with BRCA1 mutations were particularly vulnerable. BRCA1-mutant cells showed higher levels of a surface sugar (Gal-GalNAc) that helps bacteria bind to and enter a cell. Breast cells with BRCA-1 gene mutations showed increased uptake and long-term retention of F. nucleatum, even across multiple generations of cells, amplifying DNA damage and tumor-promoting effects.

“Our findings reveal a link between oral microbes and breast cancer risk and progression, particularly in genetically susceptible individuals,” says Sharma. “Nothing happens in isolation. The results suggest that multiple risk factors come together with F. nucleatum acting as an environmental factor that may cooperate with inherited BRCA1 mutations to promote breast cancer and tumor aggressiveness.”

She says further studies are needed to explore the clinical implications of these findings, and whether oral health should be considered a risk factor for breast cancer.

In addition to Sharma, other researchers on the study were Sheetal Parida, Deeptashree Nandi, Deepak Verma, Mingyang Yi, Ashutosh Yendi, Jessica Queen, Kathleen Gabrielson and Cynthia Sears.

The research was funded by the Breast Cancer Research Foundation, Congressionally Directed Medical Research Programs Department of Defense Breast Cancer Research Program grants BC191572 and BC210668), the John Fetting Fund for Breast Cancer Prevention and the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

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