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BRCA1 causes ovarian cancer through indirect, biochemical route

Mutated BRCA1 genes cause ovarian cancer indirectly, by interfering with the biochemical signals one ovarian cell sends to another, according to a team of researchers led by scientists at the USC/Norris Comprehensive Cancer Center and the Keck School of Medicine of the University of Southern California.

Their work is being published in the March 29 issue of the journal Current Biology.

"Before, we thought this gene was a classical tumor suppressor," says Louis Dubeau, professor of pathology at the Keck School and principal investigator on the paper. If that were the case, it would mean that mutation of the gene would allow the cell it's in to grow out of control and create a tumor. Instead, Dubeau notes, "What we've shown is that the gene actually acts indirectly, that it disrupts interactions between different cell types."

The well-known breast cancer gene, BRCA1, not only gives carriers of its mutated form a four in five chance of developing breast cancer, it also confers a 40 percent risk of developing ovarian cancer by the age of 70. How that risk is imparted, however, had been harder to pin down.

"We've known for a long time that ovarian cancer is associated with ovulation, in that women who have regular menstrual cycles through their life without interruption by pregnancy or oral contraceptive use are at highest risk for developing sporadic ovarian cancer," Dubeau explains. "So we had some clues that the cells that control the menstrual cycle-the ovarian granulosa cells-have an influence on ovarian cancer."

But how? Was that influence direct, or indirect? Dubeau eventually got a handle on the problem by looking at ovarian cancer rates in genetically modified mice created in collaboration with Robert Maxson, Keck School professor of biochemistry and molecular biology and director of the mouse core facility at the USC/Norris Cancer Center. "The whole project was based on creating a mouse that lacks BRCA1 in only its granulo
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Source:University of Southern California


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