In 2017, Cleveland Clinic researchers published their provocative discovery that the bacterial composition of malignant breast tissue is distinctly different from that of healthy breast tissue.
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The implications of that finding — that the localized microbiome plays a role in breast cancer — has now netted lead investigator Charis Eng, MD, PhD, Chair of Cleveland Clinic’s Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare, and her collaborators a five-year, $1.6 million grant from the Gray Foundation to further pursue the breast microbiome/cancer connection.
A better understanding of how local bacteria, fungi, viruses and the immune system interact to influence breast cancer development could impact diagnosis, treatment and prevention of the disease.
”To date we have received pilot funding, such as from VeloSano, Cleveland Clinic’s cancer research fundraising initiative, to obtain preliminary data that allowed us to be successful in the Gray Foundation’s Basser Team Science Award,” Dr. Eng says. “The new award will help us lift our research in an exponential manner. While many projects examine ‘action at a distance’ — such as the gut microbiome interacting with breast cancer, which is also important — this grant allows us to investigate the interactions of the comprehensive microbiome with the immune response. That could reveal clues to local therapies and adjunctive informed probiotics in treating early-stage and advanced breast cancers, especially in the setting of BRCA1/2 germline mutations and sporadic cancers that are BRCA-like. This holds the promise of precision oncology, with targeted efficacy and abrogated systemic toxicity.”
Dr. Eng is an internationally recognized authority in microbiome and cancer genetics translational research. Her multidisciplinary collaborators in the breast microbiome research include Stephen Grobmyer, MD, Cleveland Clinic Cancer Center’s Section Head of Surgical Oncology and Director of Breast Services, and Jacob Scott, MD, DPhil, of the Lerner Research Institute’s Department of Translational Hematology and Oncology Research.
Missing risk factors
Discovering new ways of predicting susceptibility to breast cancer is an urgent need, since more than half of women diagnosed with the disease have no known risk factors, and since only a small percentage of women with genetic predispositions or environmental-induced risk factors for breast cancer actually develop a malignancy.
Microbiome status and perturbations are a potential indicator of cancer risk. Researchers have suspected that the gut microbiome may contribute to breast oncogenesis through modification of systemic estrogen levels. Apart from the gut, Dr. Eng and her colleagues hypothesized that the localized breast tissue microbiome, as well as microbiota in other body sites, would have an altered profile from that of the surrounding normal parenchyma when cancer is present.
For their 2017 study, the researchers collected and analyzed breast, oral and urinary tract tissue from 57 women with invasive breast cancer and 21 normal controls. Bacterial gene amplification and sequencing showed that, although the tumor and benign-tissue microbiomes were largely similar in terms of diversity and content, the cancer patients’ breast microbiomes had significantly reduced populations of Methylobacterium —a microbe that produces phytohormones, some of which exert anti-cancer effects. There were no notable microbiomic differences in the oral tissue samples, but cancer patients’ urinary tract microbiomes had an increased abundance of gram-positive bacteria.
In their application for the Gray Foundation grant, Dr. Eng and her colleagues proposed to broaden their investigation of the breast microbiome to incorporate the role of fungal and viral communities, and to examine how the collective components interact with each other and the immune system to influence breast cancer growth and progression.
“Unlike most previous studies, we will move beyond simple associations and use breast cancer cell lines and mouse tumor models, including a genetically engineered BRCA1-deficient model, to investigate mechanisms that explain how microbe-immune system interactions lead to disease,” the investigators wrote. “Our work can potentially transform our understanding of breast cancer development and give rise to creative strategies” for leveraging the results into cancer-fighting approaches.
The Cleveland Clinic team’s application was one of more than 50 evaluated by the Gray Foundation, which seeks to accelerate research, improve treatment and raise awareness for BRCA-mutation breast cancers. The breast microbiome project was one of seven proposals awarded a total of $25 million in funding. Other recipients included Harvard Medical School, Weill Cornell Medicine and New York-Presbyterian/Weill Cornell Medical Center, the University of Pennsylvania, the University of Texas Health Science Center and Johns Hopkins University School of Medicine.