Signal Interference

A research finding indicates that ovarian cancer may be the result of a correctable biochemical problem.

by Lori Oliwenstein

Ovarian cancer strikes about one out of every 57 women in the United States. The vast majority of these malicious malignancies begin in the epithelium of the ovaries; this is called epithelial carcinoma.

What makes one woman more likely to get epithelial ovarian cancer than another woman is still largely a matter of conjecture. Based on data collected by epidemiologists, older women are more likely to develop ovarian cancer, as are women who have never had children. It is possible that women who take fertility drugs, women who use hormone replacement therapy after menopause, and even women who use talcum powder on their genital area are at increased risk.

There also is a genetic link. Researchers know that BRCA1—the well-known breast cancer gene—not only gives carriers of its mutated form a four-in-five chance of developing breast cancer, it also confers to them a 40 to 60 percent higher risk of developing ovarian cancer by age 85 than women who do not have this gene.

Now, researchers from the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of USC have evidence of just how the BRCA1 gene manages to wreak ovarian havoc. It works, they note, via an indirect hit—causing cancer by interfering with the biochemical signals one ovarian cell sends to another.

Their work was published in a recent issue of the journal Current Biology.

“Before, we thought this gene was a classical tumor suppressor,” says Louis Dubeau, M.D., Ph.D., professor of pathology at the Keck School and principal investigator on the paper.

A classical tumor suppressor is one that directly works to stop cells from dividing out of control; if such a suppressor were mutated—as is the case with BRCA1—it would mean that the cell would then be able to grow unchecked and create a tumor.

But that is not what is happening in ovarian cancers caused by BRCA1. Instead, Dubeau notes, “We’ve shown that the gene actually acts indirectly, that it disrupts interactions between different cell types.”

Dubeau started his work by looking at ovarian granulosa cells, which are the cells that surround the developing egg in the ovary.

“We’ve known for a long time that ovarian cancer is associated with ovulation, in that women who have regular menstrual cycles through their lives without interruption by pregnancy or oral contraceptive use are at highest risk for developing epithelial ovarian cancer,” Dubeau explains. “We had some clues that the cells that control the menstrual cycle—the ovarian granulosa cells—have an influence on ovarian cancer.”

What was not known was the precise way the cells were involved.

Dubeau eventually got a handle on the problem by looking at ovarian cancer rates in genetically modified mice created in collaboration with Robert Maxson, Ph.D., Keck School professor of biochemistry and molecular biology and director of the mouse core facility at USC/Norris.

“The whole project was based on creating a mouse that lacks BRCA1 in only its granulosa cells,” Dubeau says.

What he and his colleagues found was that while mutating the BRCA1 gene in granulosa cells did indeed give rise to ovarian tumors, those tumors did not arise in the granulosa cells. In other words, BRCA1 was not acting like a classical tumor suppressor normally should when it becomes mutated or inactivated.

Instead, when the tumor cells were analyzed, they were found to be epithelial cells similar to those found in human ovarian cancers, with perfectly intact, functioning copies of the BRCA1 gene.

“What this says is that the cells that control the menstrual cycle, the ovarian granulosa cells, also control ovarian tumor development, but from a distance,” Dubeau explains.

The most likely scenario, he says, is that the granulosa cells normally give off a chemical signal that stops the epithelial cells from growing out of control. When that chemical signal disappears due to a mutation in the BRCA1 gene, the epithelial cells do not get the message and keep growing and dividing. The result: ovarian cancer.

This finding is actually good news for scientists and physicians working on new ways to treat ovarian cancer. It implies that there is a mediator—a biochemical of some sort—that scientists might be able to replace in women with identified BRCA1 mutations, making their risk of ovarian cancer drop.

In addition, once the chemical messenger that is affected has been identified, it will be easier to diagnose a predisposition to ovarian cancer or pinpoint just who is at risk, simply by measuring the chemical’s levels.

Dubeau says, “The consequence of this finding is that BRCA1-linked ovarian cancer that is the result of some biochemical problem may be correctable or preventable. That’s what makes this finding so exciting.” ??