Scientists find why tamoxifen works better for some people

"The key takeaway from this study is that while tamoxifen is a common and important treatment for preventing breast cancer recurrence, nearly 50% of patients don't respond well to it," said lead study author Yasmine Alam, a Ph.D. candidate in the Department of Biological Chemistry, University of California Irvine. "Since tamoxifen is taken orally and passes through the gut, this difference in how patients respond may be linked to the gut microbiome -- the trillions of bacteria in our intestines, which vary greatly from person to person. Our study aims to better understand how these gut bacteria influence the way tamoxifen is absorbed, broken down and recycled in the body, with the goal of improving treatment outcomes for breast cancer patients."

In the new study, the researchers set out to define the role that gut microbes play in how tamoxifen is processed (i.e., absorption, distribution, metabolism and excretion), given its significant variable efficacy across patients. The researchers provided tamoxifen to mice that had no gut microbiome and to mice with a human microbiome (introduced to the mice by a human fecal sample). They found that mice with gut bacteria had higher amounts of tamoxifen in their bloodstream. The scientists then went on to explore what part of the gut microbiome was responsible for controlling the level of drug in the bloodstream. By examining the fecal samples from people, they linked a specific enzyme in bacteria, beta-glucuronidase, as a key factor that allows the drug to enter the bloodstream.

When a person swallows a tamoxifen pill, it passes through their stomach and into their intestines, where it is absorbed into the bloodstream. Once in the blood, tamoxifen makes its way to the liver, where the drug is changed into a form that is more effective at fighting breast cancer. However, a sugar molecule can sometimes get attached to it, which signals the body to dump the cancer-fighting form of the drug back into the intestine, instead of into the bloodstream where it can then move to the parts of the body where it needs to fight the cancer. This drug can only get out of the intestine by taking the sugar off the molecule -- and the researchers found that beta-glucuronidase in gut bacteria can eat the sugar off the drug so it can go on to fight breast cancer.

"Specifically, we found that certain enzymes produced by gut bacteria, called β-glucuronidase, play a role in how tamoxifen is broken down. These enzymes help recycle tamoxifen back into the bloodstream, which can make the drug more effective," Alam said. "We discovered that a particular type of bacteria, Bacteroides fragilis, was strongly linked to the ability of these enzymes to affect tamoxifen levels in the blood in a positive way. This suggests that the gut microbiome plays an important role in how tamoxifen works in the body."

The long-term goal of the study is to pave the way for more tailored and effective therapeutic interventions in the prevention of breast cancer recurrence.

The study was led by Elizabeth Bess, Ph.D., assistant professor in the department of chemistry at UC Irvine, and Cholsoon Jang, Ph.D., assistant professor in the department of biological chemistry at UC Irvine.