Researchers at the Wistar Institute in Philadelphia report today in Cell that they have found a new gene that may contribute to some cases of inherited breast cancer. Scientists tracked down the first so-called breast cancer gene, BRCA1, in 1994; the discovery of BRCA2 came soon thereafter. Mutations in these two genes account for most familial cases of breast cancer, which make up 5 percent of the estimated 180,000 new diagnoses each year. Still, scientists have struggled to figure out how the different mutations lead to disease. The new study reveals that BRCA2 plays an importantand previously unsuspectedrole in cell division. Moreover, the BRCA2 protein interacts with the product of a new gene, christened BRAF35, forming a novel protein complex.
Earlier studies of BRCA2 suggested that it was involved in DNA repairwhich the new results do not contradict. They do, however, add to the genes' functionality. "The complex in which we find BRCA2 and BRAF35 might serve a dual purpose for the cell," senior author Ramin Shiekhattar says. "It could be involved in both processes, DNA repair and cell cycle progression. Evolution often finds a way to use these complexes as tools for more than one task, like an Allen wrench or a Swiss Army knife."
Shiekhattar and colleagues set out to establish how BRCA2 and BRAF35 influenced cell cycle progression. To do so, they first used a drug to stop a group of dividing cells at the same stage, and then removed the drug. Next they neutralized the activity of either the BRCA2 or BRAF35 protein in some of the cells using custom antibodies. After 12 hours, they found that some 80 percent of the control cells had moved through mitosisa stage of cell division. In contrast, only half of both the BRCA2- and BRAF35-neutralized cells had done so. After 14 hours, 90 percent of the controls had completed mitosis, whereas the neutralized cells continued to lag behind.
"Interestingly, the effect of neutralizing these two proteins was a significant delay in mitosis, but it was not a full block of the cell-division process," Shiekhattar says. "The fact that both antibodies appeared to be doing exactly the same thing gave credence to the idea of a functional interaction between these two proteins, and indicated they were involved in the same process."