Breast Cancer Lead: Overactive gene is linked to disease

Researchers have discovered a new breast cancer gene that’s overly active in 30 to 40 percent of women with the disease. The high percentage makes the malfunctioning of this gene, called I-kappa-B kinase epsilon (IKBKE), one of the most widespread genetic traits among breast cancer patients, says William C. Hahn, coleader of the research team at the Broad Institute in Cambridge, Mass. Their study appears in the June 15 Cell.

Most cancer-related mutations are present in less than 10 percent of women with breast cancer, and only a few important ones characterize as much as 30 percent of that population.

The discovery gives drug companies a significant new target for breast cancer drugs. In addition, the study proved the value of a novel way for scientists to screen any kind of tumor for key cancer-causing mutations.

IKBKE is normally active only in immune system cells, where it helps trigger a response to invading viruses. It has no known function in healthy breast cells, but if a DNA mutation causes the gene to become active, it may signal a cell to proliferate out of control.

The team used a three-step screening process to find the gene. First, the scientists injected each of 354 candidate enzymes into normal, cultured breast cells to see which enzymes would induce cancer. Five of them did so. Then the group checked whether the genes that make those five enzymes were overly active in cells taken from tumors in 30 breast cancer patients. Of the genes, only IKBKE showed elevated activity, and this occurred in 30 percent of the patients’ cancers. The researchers then studied tumors from 200 other breast cancer patients and found the enzyme produced by IKBKE in 40 percent of the samples.

In the third step, Hahn’s team blocked the gene with a snippet of interfering RNA. With IKBKE blocked, the cancerous cells slowly withered and died, indicating that the cells depended on it for survival.

“I actually think [the new study] is a pretty big deal,” says Gordon Mills of the M.D. Anderson Cancer Center in Houston. “I doubt that there are many more [breast cancer] genes of this magnitude to be found.”

The cancerous cells contained a mutation that produced 5 to 10 extra copies of IKBKE, but it remains unclear exactly how that mutation happens or what puts a person at risk of it. “We can say they’re amplified or mutated, but we really can’t say why,” Hahn explains.

Developing a drug to target IKBKE should be possible, Hahn says, because the enzyme that it produces is a so-called kinase. “Drug companies have a lot of experience at making drugs that can inhibit this class of kinases,” he says.