New research from the University of Virginia has found that an unhealthy gut microbiome can increase the spread of breast cancer.
A new in the journal Cancer Research found that a buildup of bile acids caused by an unhealthy gut can spread hormone receptor-positive breast cancer to other parts of the body.
A professor at the UVA School of Medicine, Melanie Rutkowski leads a lab focused on studying tumor growth and metastasis. (Contributed photo)
The research team was led by Melanie Rutkowski, an associate professor of microbiology, immunology and cancer biology, who corresponded with UVA Today about the discovery and potential treatments.
Q. What is hormone receptor-positive breast cancer?
A. Hormone receptor-positive breast cancer is the most common subtype of breast cancer, defined by the presence of receptors for estrogen and/or progesterone on the tumor cells. These receptors allow breast tumors to grow in response to these hormones, which is why treatments for this type of breast cancer work by blocking the receptors or lowering the body’s estrogen levels. These therapies have greatly improved outcomes.
However, there is still a large proportion of women diagnosed with hormone receptor-positive breast cancer who will eventually experience recurrence and develop metastatic disease. In fact, a majority of patients with metastatic breast cancer were initially diagnosed with hormone receptor-positive disease. This means that metastasis/recurrence is still an unmet problem for this subtype of breast cancer.
One gap in knowledge our lab is trying to address is why some women go on to develop metastatic disease while others remain progression-free, despite being diagnosed with the same grade/stage of disease. We believe a previously overlooked factor is gut health, specifically, the gut microbiome.
Q. What is the connection between an unhealthy gut microbiome and breast cancer spread?
A. The liver produces bile acids, which are molecules that help in the digestion of fats. However, the bile acids do not work alone; once they reach the gut, certain bacteria transform them into different forms, which helps to regulate how much circulates in the body, creating a constant back-and-forth between the gut and the liver. When the gut microbiome is unhealthy, you lose many of the bacteria responsible for this processing, which disrupts the back-and-forth communication, leading to an abnormal balance of bile acids throughout the body.
What we found is that this loss of bacteria causes a buildup of the primary bile acids that those bacteria would normally transform. Bile acids aren’t just for digestion; they’re potent signaling molecules that can influence the behavior of cells in the body, including immune cells. We found that this disruption in gut health and bile acid levels led to inflammatory changes in breast tissue and the lungs that are known to support breast tumor metastasis.
Q. Did you find any methods to counteract this?
A. Yes, the exciting part is that there are already FDA-approved drugs called bile acid sequestrants that control bile acid levels by binding them in the gut so they’re excreted in the feces. When we gave these drugs to mice with an unhealthy gut, metastatic spread was significantly reduced. These drugs are generally well-tolerated, suggesting they could be administered to improve outcomes for women with metastatic disease.
When we analyzed patient records for women diagnosed with metastatic hormone receptor-positive breast cancer, we found that those who were taking bile acid sequestrants had significantly longer survival than those who were not. These clinical findings were consistent with the data we generated using the mouse model.
What we need to do now is understand whether bile acid sequestrants are a viable strategy to prevent breast cancer metastasis.
Q. In addition to working with mice, you also developed a human study. What was your methodology?
A. For the human studies, we used two different approaches. We used one approach to tell us what is happening at the molecular level inside tumors, and then we used a second approach to tell us what is happening to patients in the real world.
To tell us what is happening at the molecular level inside tumors, we used the Cancer Genome Atlas. The TCGA was a government-funded project that molecularly characterized over 20,000 tumors across 33 cancer types, creating what is essentially a public reference library of cancer that researchers use to connect molecular features to patient outcomes. We used this database to analyze whether tumor expression levels indicative of bile acid signaling affected survival for women with metastatic breast cancer. We found that breast tumors having high expression signatures of bile acid signaling had significantly reduced survival compared to those with lower levels of bile acid signaling.
