TLR5 Polymorphism Enhances Luminal Breast Cancer Progression

TLR5 Polymorphism Enhances Luminal Breast Cancer Progression

shutterstock_214055650Certain common DNA variations, called polymorphisms, can determine how tumor progression evolves in breast cancer and other types of cancers, including ovarian cancer. Researchers at The Wistar Institute, led by José Conejo-Garcia, MD, PhD, determined that a polymorphism that occurs in 7.5% of the general population–one in fifteen people–affects Toll-like receptor (TLR) genes and makes individuals more susceptible to compromised immunity against cancer.

“Our research indicates that interactions between the helpful bacteria in our bodies and immune cells at places situated away from tumors influence systemic responses in the host that alter how these tumors are able to progress,” said Dr. Conejo-Garcia in a news release from The Wistar Institute.

Apparently, there is an explicit relationship between the trillions of bacteria that colonize humans and tumor progression. The “good” bacteria that inhabit the gastrointestinal and respiratory tracts and the skin are not only a first line of defense against infection, but also an important defense against tumors outside the intestines.

Dr. Conejo-Garcia’s work focused specifically on TLRs. In order for a hosts’ immune system to recognize invaders, human cells use TLRs to find pathogen-associated molecular patterns on surfaces that come in contact with the cells. It is known that when polymorphisms are present in TLR genes, the immune system can leave invaders unnoticed and lead to diseases such as urinary tract infections and Legionnaires disease, but Dr. Conejo-Garcia was interested in how TLR5 signaling can influence cancer, in particular breast cancer.

From a mechanistic standpoint, the team at The Wistar Institute found that TLR5-dependent commensal bacteria secrete interleukin-6 (IL-6) to activate myeloid-derived suppressor cells that can in turn stimulate gamma delta T cells to secrete galectin-1. This molecule suppresses antitumor immune activity, allowing tumor cells to survive and progress. Removing commensal bacteria with antibiotics erased the differences in TLR5-mediated tumor progression.

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Delving further, the team found that TLR5-deficienct mice carrying tumors have low levels of IL-6, but high levels of IL-17 that can accelerate cancer progression independent of TLR5 signaling. All results were published in Cancer Cell, under the title, “Microbially Driven TLR5-Dependent Signaling Governs Distal Malignant Progression through Tumor-Promoting Inflammation.”

As a final result, the team conducted a survival analysis using The Cancer Genome Atlas database for patients with listed TLR5 status. Patients with luminal breast cancer–a cancer associated with low circulating IL-6–had poor long-term survival when TLR5 was absent. “Although independent sets of data and higher numbers of patients are needed, our data suggest that ovarian cancer reflects the evolution of IL-6 dependent tumors, while luminal breast cancer appears to become more aggressive in carriers of the polymorphism that abrogates TLR5 signaling,” concluded Dr. Conejo-Garcia.