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Closing in on cancer

Researchers discover an enzyme that causes mutations in breast and other cancers, shedding new light on a cure.

October 23, 2013

It's well known that sunlight and chemical carcinogens can mutate DNA, and that mutations are essential for cancer to develop. One big mystery was what causes the thousands of mutations evident in most breast cancers.

Earlier this year researcher Reuben Harris and his colleagues found evidence that one of our own proteins is a major source of these mutations. The researchers published evidence implicating the protein—an enzyme called APOBEC3B—in the international journal Nature.

Rueben Harris

"We discovered a rogue DNA-mutating enzyme in more than half of breast cancers. This is the first clear example of enzyme-induced mutations in human cancer," says Harris, a professor of biochemistry, molecular biology and biophysics in the College of Biological Sciences and a member of the Masonic Cancer Center, University of Minnesota. "With this knowledge, we now have a chance to do something about it.

"An obvious next step is to determine how early APOBEC3B starts contributing to mutation in breast cancer, and figuring out ways to suppress the accumulation of these mutations. This could have a major impact—for instance, in decreasing the chance of tumors developing resistance to therapeutic drugs."

Now, Harris and his colleagues have extended those findings to other cancers. In a study encompassing 19 different cancer types and a million mutations, the researchers found similar evidence for APOBEC3B as a contributor to the mutational load of six types of cancer: bladder, cervix, head &neck, and two forms of lung cancer, as well as breast. That work is published in the journal Nature Genetics. Additional work focused on ovarian cancer was published recently in the journal Cancer Research.

"We are very excited about these discoveries because they indicate that a single enzyme is one of the largest known contributors to mutagenesis in cancer, definitely eclipsing sources such as UV rays from the sun and chemicals from smoking," says Harris.

Calling card for cancer?

APOBEC3B belongs to a family of enzymes called APOBECs (A'-po-becks). They function, earlier work in Harris's lab found, to mutate DNA. Some, active in white blood cells, mutate HIV-derived DNA as a first line of defense against the virus. APOBEC3B also seems to act normally against viruses and other parasitic elements.

But Harris and his colleagues turned up several pieces of evidence pointing to APOBEC3B as a source of mutations in breast cancer. For example, they discovered elevated APOBEC3B levels in many breast cancer cell lines and fresh breast tumor cells (but not normal breast cells) they studied. And disabling the gene for APOBEC3B in breast cancer cell lines slashed the number of mutations and established clear cause and effect.

They further showed that APOBEC3B tends to mutate DNA in a certain pattern, which is imprinted all over the genomes of many different cancer types and is equivalent to a "signature" or "calling card."

Gutting a guardian

Consider one of the best-known "cancer genes," TP53, which functions to suppress cancer and is often referred to in scientific circles as "the guardian of the genome." In their earlier study the researchers worked with large data sets and found it is mutated—and inactivated—in breast tumors with high APOBEC3B activity.

The best explanation for this, says Harris, is that something turns on APOBEC3B activity in cells that are otherwise healthy. It then mutates the TP53 gene and inactivates it, unleashing a chain of events that results in cancer.

"We showed that APOBEC3B causes chromosomal damage and mutagenesis," Harris explains. "Also, we see higher APOBEC3B activity at all stages of breast cancer, implying it's an early event. So we favor APOBEC3B as the cause of TP53 inactivation."

Inessential gene, enigmatic enzyme

"APOBEC3B is a double-edged sword," says Harris. "It's a really good [antiviral] enzyme, but its DNA-mutating activity can also be detrimental to the cell. Obviously, this has been balanced by evolution, and it generally doesn't become a problem until near the end of reproductive age."

But it isn't essential for life; although present in many Europeans and individuals from sub-Saharan Africa, the gene for APOBEC3B is lacking in many Pacific Islanders and Asians, notably Japanese, who have lower rates of breast cancer.

Harris would like to know how the absence or presence of APOBEC3B and its gene correlates with cancer risk and other factors. Also, he hopes to find a way to block the enzyme from mutating DNA, much as sunscreen prevents mutations in skin. And by focusing on APOBEC3B, researchers may be able to zero in on factors that act earlier in the sequence of events leading to cancer, by causing APOBEC3B to run amok and/or by causing other events that would be amenable to therapy.

"We are confident that our findings will trigger a domino effect of additional research and clinical studies that result in better outcomes for patients with many forms of cancer," Harris says.

Watch the interview with cancer survivor Debra Dowd

Contact the writer at morri029@umn.edu.

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