Hereditary forms of breast cancer on the trail

Mutation in risk gene allows DNA duplication to run

Breast cancer cell under the electron microscope © NCI
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When the genetic material breaks, cancer threatens. Those who inherit a mutant gene may already have a greater genetic predisposition to cancer. In the case of breast cancer, several such risk genes are known in which mutations can lead to further damage. How it finally comes to the cancer, but so far was not yet known. In the journal "Nature Communications", a research group from Germany and Finland is now reporting on a mechanism that is responsible for early stages of breast cancer development: The affected cells are too stressed and hectic to double their DNA before they divide.

Hereditary risk due to gene mutation

With around 72, 000 new cases annually, breast cancer is by far the most common cancer among women in Germany. A variety of genes play a role in increased hereditary predisposition. In 5-10% of hereditary breast cancer cases, a mutation of the breast cancer associated genes BRCA1 and BRCA2 is considered responsible. These genes are important for the repair of DNA damage. Another important candidate is the gene PALB2.

An international team led by Helmut Pospiech from the Leibniz Institute for Age Research in Jena and Robert Winqvist from the University of Oulu in Finland now investigated how mutant PALB2 cells behave in cell division experiments. The researchers used specimens from women, all carrying the same PALB2 mutation. Some of these women were already suffering from breast cancer, the others were completely healthy. From this material, the team bred cell cultures and analyzed how the cells double their genome and divide.

Mutant gene produces half as much protein

From previous work it was known that the PALB2 protein binds to BRCA2 and stabilizes its chromatin binding. This support is important for the repair of chromosomal fractures. PALB2 also controls the interaction between BRCA1 and BRCA2 in homologous recombination, a DNA repair mechanism of the cell. However, the mutation causes only half as much PALB2 in the cells as normal.

The researchers were able to show that this lack of mutated cells replication, the duplication of DNA, disturbed. "Of the approximately 250, 000 defined locations where replication can start, only about ten percent are actually used. The remainder serves as a kind of quiet reserve to withstand stress and other disruptive factors, "explains biochemist Pospiech. If problems occur when doubling, the replication stops and restarts at a starting point nearby. In addition, the "sleeping" reserve is awakened. display

Genetics knitted with hot needle

However, it is precisely this reserve that is likely to be a threat to the mutant cells: In contrast to the control cells, we found that the cells of mutation carriers start replication twice as often, thereby accelerating the rate of replication Often replication does not go through to completion in many places; The DNA is almost doubled as with a hot needle, "continues Pospiech. With fatal consequences, because this can lead to more errors, as important control mechanisms are bypassed.

The researchers showed that DNA replication in the mutated cells increasingly relies on the hidden reserve without any external disturbance or stress being the trigger, On the other hand, if real stress occurs, the cells can no longer respond because their reserves are already exhausted.

Mutated cells run out of steam

During the cell growth process, various checkpoints check that all processes have been properly completed and that any damage has already been removed. Only then does the next phase of cell division begin. When damage is done to the cells, the mutant cells can not sustain a robust DNA damage response for long. "The mutated cells go out of breath after a few hours, so that defective cells are released and ultimately chromosomal damage occur, " emphasizes Pospiech. The PALB2 mutation makes the cells drastically more susceptible to permanent damage. This destabilization of the genetic material can ultimately lead to breast cancer.

(Nature Communications, 2013; doi: 10.1038 / ncomms3578)

(Leibniz Institute for Age Research, 25.10.2013 - AKR)