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Switching gears

Masonic Cancer Center researcher Reuben Harris, Ph.D., identified a protein that appears to be a driver for more than half of breast cancers. Now he's investigating the protein's role in other types of cancer as well. (Photo: Scott Streble)

Longtime HIV researcher makes a breakthrough cancer discovery

“Mutant variants of human cells”: the phrase conjures up images of a bad sci-fi movie. But Reuben Harris, Ph.D., a member of the Masonic Cancer Center, University of Minnesota, has been studying cell mutations for more than 20 years, and his recent finding is more akin to an Oscar-winning blockbuster.

So remarkable is his work that the prestigious journal Nature—widely considered the journal of note for scientists—in February published his discovery that a protein that occurs naturally in the body appears to be a driver for more than half of breast cancers he studied. This breakthrough could lead to new diagnostic tools and, potentially, new treatments for breast cancer.

Harris’s finding has its roots in HIV research. His team has been exploring the role that seven proteins known as APOBEC3s play in the body’s fight against HIV infection.

“My lab studies mechanisms of mutation,” explains Harris. “Specifically, we’ve been looking at mechanisms that impact the evolution of HIV, which is like a chameleon hiding in the genomes of our bodies, mutating rapidly to resist treatment.”

In the course of that work, Harris—also an associate professor of biochemistry, molecular biology, and biophysics at the University—had an epiphany. What, he wondered, were those seven proteins up to in “normal” cells not infected with HIV? And what part might they play in diseases like cancer?

In research supported by the National Institutes of Health, students in his lab invented highly sensitive tests that allowed them to measure the expression levels of each one of these genes specifically.

“That was really key because these seven proteins are closely related to one another,” Harris says, “and they were very difficult to detect and measure.”

With this new measuring ability in hand, and with seed grant support from the University’s Clinical and Translational Science Institute, the team compared the APOBEC3 proteins in both breast cancer cells and healthy cells from the same person and found an anomaly: one of the seven—APOBEC3B—was turned on in many of the breast cancers studied, yet it was virtually undetectable in normal breast tissue.

“Additional experiments showed that this protein was mutating the genome of the cancer cells,” Harris says. “And without mutation, there is no cancer. So this protein, we postulate, may be a key driver of cancer.”

In other words, what Harris’s team discovered is a new source of mutation.

“We know sun causes mutation,” Harris says. “We know certain chemicals cause mutations. But for the first time, we’ve identified an enzyme in our own bodies that causes a large number of mutations. How do we protect against an in-built source of mutation? You can’t slather on sunscreen to protect against this.”

Harris’s discovery, made in collaboration with Masonic Cancer Center director Douglas Yee, M.D., and colleague Natalia Tretyakova, Ph.D., could have a profound impact on physicians’ ability to diagnose some breast cancers: Take a tissue sample, and if this protein is overexpressed in the sample, there’s a strong likelihood that it’s cancerous.

“A next step would be to find the APOBEC3B ‘sunscreen,’” says Harris. “Find out what slows down or stops this enzyme.”

Researchers already know that it can be done. Harris’s lab has identified compounds that can slow down the activity of related APOBEC3 enzymes, and he speculates that this can also be done for APOBEC3B.

But can it be done in a human body with an active metabolism? That, he says, is yet to be determined.

Harris isn’t taking time to bask in the glow of his Nature publication. He and his colleagues have more work to do.

“Once something like this comes out, hundreds of other researchers will take notice, which helps move things along a lot faster,” Harris says. “And for everybody out there with APOBEC3B-positive breast cancer, a community effort will be crucial for translating this discovery into real clinical benefits.”

For more information about this or other breast cancer research at the Masonic Cancer Center, contact Kathy Beenen at 612-625-6495 or kbeenen@umn.edu.

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